Reprinted from The British Medical Journal Online, September 2003
Low CD4 Counts: A Variety of Causes and Their Implications
to a Multi-factorial Model of AIDS
By Matt Irwin, MD
“So many different conditions are associated with
profoundly reduced CD4 counts. The fact that HIV-negative people
with many common conditions like mononucleosis, pregnancy, and pneumonia
can have levels below those needed to diagnose AIDS suggests the
use of CD4 counts in persons testing HIV positive should be carefully
I personally believe in a multifactorial model of AIDS. I think
that even if there were a new virus that could be adequately identified
by the current "HIV tests,” it would be only one of many
factors causing immune dysfunction. If HIV is one of these factors,
I do not believe that it is enough by itself to cause AIDS. I also
believe that the HIV positive diagnosis becomes a self-fulfilling
prophecy, which is the main reason I have become active in this
I use the word "believe" because I recognize that my ideas
are not proven to be true, nor do I think that anyone should try
to prove them, as this would involve unethical experiments. Instead,
I intend to show that this multifactorial stance is more likely
than the conventional stance that HIV is the sole cause of AIDS,
and that the conventional stance is based almost entirely on faulty
assumptions that have been repeatedly contradicted in the medical
Finally, my fundamental belief about HIV and AIDS is that people
should have a right to choose their source of information as well
as make their own decisions about what to do for their own health.
This also applies to the parents of children who are HIV positive
and pregnant women who test HIV-positive. If they want to take anti-retroviral
medications or make their children take them in spite of the inherent
risks, that is their right. If they endorse natural health measures
and reject the idea that “HIV=death,” as I do, then
that is also their right.
The following shows that the complete clinical picture of AIDS commonly
occurs in the absence of HIV. There are so many different conditions
that cause low CD4 counts that it appears that it is a non-specific
reaction to just about any physical or psychological stressor. There
is thus no need to postulate the presence of a new virus to explain
low CD4 counts, which are extraordinarily common.
Low CD4+ T lymphocyte counts (CD4 counts) are associated with a
variety of conditions, including many viral infections, bacterial
infections, parasitic infections, sepsis, tuberculosis, coccidioidomycosis,
burns, trauma, intravenous injections of foreign proteins, malnutrition,
over-exercising, pregnancy, corticosteroid use, normal daily variation,
psychological stress, and social isolation. It is also possible
that anti-HIV medications can lower CD4 counts when used for long
periods, and the short term rise in CD4 counts that is associated
with their use may be due to a variety of factors that are unrelated
to any anti-HIV activity. Finally, there are a number of people
who are completely healthy and who have low CD4 counts for no apparent
reason. This paper presents a brief review of several studies documenting
low CD4 counts in people who are experiencing such conditions. The
low CD4 counts caused by some of these conditions often fall below
200 per cubic miliimeter, which is the level needed to diagnose
acquired immunodeficiency syndrome (AIDS) in someone who was previously
positive for antibodies to the human immunodeficiency virus (HIV-positive).
In addition to its use in making a diagnosis of AIDS, CD4 counts
are regularly used to make treatment decisions in people diagnosed
HIV-positive, such as when to start antiretroviral medications and
when to begin preventative antibiotics.
Because many of the conditions that cause low CD4 counts are common
in people diagnosed HIV-positive, caution is advised regarding the
use of CD4 counts to make treatment and diagnostic decisions. This
is made more urgent since some of the conditions, like psychological
stress, are greatly increased when people are told that their CD4
counts are low, which may compound the problem and cause the CD4
count to fall even further. Psychological stress and social isolation
are also created by the diagnosis of HIV-positive, and by the diagnosis
of AIDS, which may have chronic effects on the CD4 count. Finally,
the widely accepted argument that HIV specifically targets CD4+
T lymphocytes is also called into question, because it appears that
low CD4 counts are a common reaction to many kinds of physical and
psychological stressors. Other alterations in immune system parameters
which are thought to be specific to HIV are also replicated extremely
well by the conditions to be reviewed, making it impossible to distinguish
any effects attributed to HIV that could not also be caused by these
other factors. When several of these factors are combined, as is
often the case in people diagnosed HIV-positive, extremely low CD4
counts may be a natural result.
Low CD4 T-cell counts are considered to be a marker of the progression
of HIV infection and AIDS, and have been called the 'hallmark' of
HIV (Balter 1997). Since HIV was first claimed to be the cause of
AIDS in 1984, the CD4 count has been widely used to make treatment
and diagnostic decisions, but the use of the CD4 count has been
controversial, and recommendations regarding how to use them have
changed many times over the years (Goldman 2000, Hughes et al. 1998,
Choi et al 1993).
In addition to low CD4 counts, the CD4/CD8 ratio is also considered
a marker of disease progression in HIV and AIDS, and is often found
to be inverted. An 'inverted' ratio simply means that there are
less CD4 cells than CD8 cells, resulting in a ratio of less than
1. CD8 cells are often increased, especially in less advanced stages
of AIDS, and this combination of lowered CD4 counts and increased
CD8 counts are commonly thought to occur only in people diagnosed
HIV-positive. Another finding that is common in people diagnosed
HIV-positive is reduced lymphocyte activity and function, as measured
by their responsiveness to foreign antigens. This can result in
a state of "anergy", where people's skin fails to respond
when antigens are injected under it. As this paper will demonstrate,
all of these changes are common in a wide variety of conditions
that commonly occur to people diagnosed HIV-positive.
There are two major arms of the immune system; one works through
antibodies produced by B-cells and plasma cells, and the other works
through direct cellular action and relies heavily on CD4+ T-cells.
The first is called antibody-mediated or humoral immunity, and the
second is called cell-mediated immunity. It is the cell-mediated
arm of the immune system that is profoundly suppressed in people
diagnosed with AIDS. The antibody-mediated arm of the immune system,
however, is usually hyper-stimulated in the early stages, with "increasing
levels of humoral antibodies and plasma cells (Fox 1996).”
The fact that antibody levels are increased is what allows the HIV
antibody screening tests to use serum that has been diluted 400
times, unlike other antibody tests that use straight, undiluted
serum (Abbott Laboratories 1997). In these early stages the lymph
nodes may grow in size and be chronically enlarged. In late stages,
however, both the cell-mediated and antibody-mediated arms of the
immune system begin to fail, and lymph node atrophy results. The
only measurement commonly used in clinical practice, however, is
the CD4 count, as the following treatment and diagnostic recommendations
demonstrate (Cecil Textbook of Medicine, Goldman 2000):
"Over the years, the recommendations of when to begin therapy
for HIV have fluctuated back and forth, and a prior trend to treat
most patients with fewer than 500 cells/mm3 with zidovudine (AZT)
was modified by the results of a large randomized study (the Concorde
Trial) showing that early AZT therapy did not yield improvement
in survival. (Goldman 2000, page 1939)
“When the CD4 count in someone diagnosed HIV-positive is found
to be below 200, AIDS is diagnosed. This method currently accounts
for over half of all AIDS diagnoses, and so is highly significant
“There are two approaches regarding when to start antiretroviral
therapy. The more aggressive approach recommends starting when the
CD4 count falls below 500, and the second approach is to wait until
it is below 350 unless the viral load is also above 20,000 copies
per ml. The more aggressiveapproach is more commonly used in the
United States, and many clinicians will even start antiretroviral
medications immediately in all patients, regardless of the patient's
“To prevent pneumocystis carinii pneumonia (PCP), antibiotics
should be started if the CD4 count is found to be below 200. The
most commonly used combination is sulfamethoxazole/trimethoprim
(SMX/TMP), commonly referred to by its brand name, Bactrim.
“To prevent fungal infections, the antifungal medication fluconazole
should be started if the CD4 count is below 200.
“To prevent mycobacterium avium complex (MAC) infection, the
antibiotics clarithromycin, azithromycin, or rifabutin should be
started if the CD4 count is below 100.
“To prevent cytomegalovirus (CMV) infection, oral gancyclovir
can be started, although no CD4 level or other guideline is given.”
Newer recommendations from the National Institute of Health presented
in February, 2001 call for a halt to the widespread practice of
starting antiretroviral medications immediately, regardless of the
patient's health status or CD4 count (Garrett 2001). This marks
a retreat from the "hit hard, hit early" approach advocated
by David Ho and others since 1996 when protease inhibitor combination
therapy was begun. The change is recommended because of the
toxicities of the drugs, the severity of adverse effects and the
difficulty in staying on them for long periods of time.
While most people know about the reports of lowered CD4 levels in
people diagnosed HIV-positive, which continue to receive widespread
press coverage, other reports concerning lowered CD4 counts in people
who are HIV-negative have been widely ignored. These reports show
that CD4 counts commonly fall extremely low, especially if a person
suffers from certain conditions. These conditions include a variety
of viral illnesses, bacterial infections, parasitic infections,
sepsis, septic shock, multiple organ system failure, tuberculosis,
coccidioidomycosis, burns, trauma, transfusions, malnutrition, over-exercising,
pregnancy, normal daily variation, psychological stress, and social
isolation. In addition to lowered CD4 counts, other immune system
changes occur that are also identical to those seen in people diagnosed
HIV-positive, including reduced CD4/CD8 ratios, increased CD8 cells,
reduced lymphocyte function, anergy, increased antibody levels,
atrophy of lymphoid organs, and general suppression of cell-mediated
immunity. These effects can take weeks or months to return to normal,
and, if there are recurrent infections or if multiple factors are
present, the low CD4 count could take much longer than this to correct,
or may even stay low indefinitely. Finally, the drugs used to treat
HIV commonly cause a dose dependent immunosuppression, as well as
other side effects that can may be blamed on HIV, and this has been
made clear by strongly worded warnings from the drugs' own manufacturers.
Several studies that examine these adverse effects will be reviewed
here and studies will be emphasized if they reveal either lowered
absolute CD4 counts, lowered CD4 percentages, or a reduced CD4/CD8
ratio, since these are most often thought to be specific to HIV
1) Low CD4 counts in the intensive care unit
In 1995, Feeney et al. looked at CD4 counts in 102 consecutive intensive
care unit (ICU) patients who were admitted for a variety of reasons,
all of whom were HIV negative. The patients suffered from 34 different
illnesses, with the most common being myocardial infarction (heart
attack), severe bleeding, renal failure, trauma, and chronic pulmonary
disease. 30% of these patients had CD4 counts less than 300, and
41% had CD4 counts less than 400. The authors do not discuss how
many had counts below 200, the level resulting in a diagnosis of
AIDS, or exactly how many had counts below 500, the level at which
antiretroviral medications would be started in someone who has been
diagnosed HIV-positive. They also did not find that low CD4 counts
were linked with a poor prognosis. Here are the author's comments
on their findings:
“Our results demonstrate that acute illness alone, in the
absence of HIV infection, can be associated with profoundly depressed
lymphocyte concentrations. Although we hypothesized that this depression
would be directly related to the severity of illness, this was not
seen in our results. The T-cell depression we observed was unpredictable
and did not correlate with severity of illness, predicted mortality
rate, or survival rate. This study was consistent with prior studies
that have shown similar decreases in T-cell counts in specific subsets
of acutely ill patients. These subsets included patients with bacterial
infections, sepsis, septic shock, multiple organ system failure,
tuberculosis, coccidioidomycosis, viral infections, burns, and trauma
patients. Most of these studies reported decreases in lymphocyte
populations, some of which were severe and included CD4/CD8 ratio
In the largest study to date of hospitalized patients, Williams
et al (1983) evaluated T-cell subsets in 146 febrile patients with
serious acute infections with 19 of 45 patients having a CD4 count
of less than 300 per microliter.
We also found that CD4 counts were linearly related to total lymphocyte
concentrations, as Blatt et al. (1991) reported in HIV-positive
patients. (Feeney et al. 1995, pages 1682-1683)
These researchers did not find that low CD4 cell counts were good
measures of prognosis, although some other reports differ in this
2) Low CD4 counts in various human infections
2a) Pneumonia, pyelonephritis, abscesses, infected wounds,
cellulitis, and sepsis
In 1983, about one year before HIV was first mentioned as a possible
cause of AIDS, Williams et al. published a study showing severely
reduced CD4 counts in 146 consecutive people with serious acute
infections who were admitted to their hospital in New Mexico. This
article was referred to in the article by Feeney et al. that was
reviewed above. The infections included pneumonia, acute pyelonephritis,
abscesses, infected wounds, cellulitis, deep tissue infections,
The authors only provide average CD4 counts for the majority of
patients, except for a graph that plots the CD4 counts for all 45
pneumonia patients. This reveals that 31 of 45 (69%) had CD4 counts
less than 500 cells/mm3, 19 of 45 (42%) had counts below 300, 13
of 45 (29%) had counts below 200, 6 of 45 (13%) had 100 or less,
and 2 of 45 (4%) had values less than 50. The average CD4 count
for all the people with pneumonia was 574. Although CD8 cells were
mildly reduced, the CD4/CD8 ratio was often inverted as seen in
AIDS, and the authors caution against using CD4/CD8 ratios to evaluate
AIDSpatients: "We caution that because infection itself often
results in helper-suppressor ratios of less than 1.0, ratios alone
cannot be used to define the presence of profound acquired immunodeficiency"
(Williams et al. 1983, page 815).
The authors provide tables with clinical information and CD4 counts
for 9 patients with soft tissue infections (STI) and 12 patients
with sepsis/deep infections, all of whom had multiple T-cell abnormalities.
Brief descriptions of all the cases from these tables who had CD4
counts less than 200 follow:
- a 25 year-old female with "disseminated varicella",
CD4 count of 58, "rapid septic course, death".
- a 41 year-old male with Group A hemolytic streptococcal sepsis,
CD4 count of 150, "rapid progression, ... death".
- a 42 year-old male with E-coli sepsis, CD4 count of 156, "Multiple
previous episodes of E-coli bacteremia".
- a 38 year-old female with a submandibular abscess, CD4 count of
183, "Gram-positive organism, short 5-day hospital stay".
- a 46 year-old man with peritonitis, CD4 count of 205, who was
on long-term peritoneal dialysis.
- a 58 year-old female with infected decubitous ulcers, CD4 count
of 189, "prolonged 4-month hospital stay, ... E-coli and pseudomonas
- 75 year-old female with a common duct stone and ascending cholangitis,
CD4 count of 139, "multiple positive blood culture results".
These case examples are notable in that some of them sound very
similar to people who die of AIDS, such as the 25 year old female
who died of disseminated varicella with a CD4 count of only 58 cells/mm3.
Others, such as the 38 year old female with an abscess and CD4 count
of 189 who was releasedafter a "short 5-day hospital stay"
suggest that many people with extremely low CD4 counts can achieve
quick recoveries. It is also remarkable that 30% of people with
pneumonia, which is a very common illness in people diagnosed HIV-positive,
had CD4 counts below 200, and 70% had counts below 500. These authors
did find some correlation between severity of illness and CD4 counts;
patients with sepsis who recovered also had gradual increases in
CD4 counts, while those that died had counts that remained low.
2b) Low CD4 counts in malaria
Malaria is caused by parasites from the plasmodium species, and
is extremely common in Africa and in many tropical areas. In 1999
a letter was published documenting severely lowered CD4 counts in
African patients with malaria (Chirenda 1999). The author examined
the CD4 count in 78 patients with malaria who were HIV-positive,
and 19 who were HIV-negative. He was surprised to find that more
HIV-negative malaria cases had severely lowered CD4 counts than
did the HIV-positive cases, on average, with 8 of 19 (42%) HIV-negative
cases being below 200, while only 31 of 78 (40%) HIV-positive cases
had CD4 counts below 200. Seven HIV-negative malaria cases had CD4
counts below 100. In addition, 6 HIV-positive patients had normal
CD4 counts. The author states, "One may want to hypothesise
that malaria reduces the CD4 count more than HIV infection.”
The author did not do statistical analyses to test for statistical
significance, nor does he mention the general health or nutrition
status of the patients which may have contributed to their severely
lowered CD4 counts as will be reviewed later in this paper.
2c) Low CD4 counts in mononucleosis
Mononucleosis (also called 'mono') is a common viral illness, especially
in young people of college age, and can last for several months.
It is caused by cytomegalovirus (CMV) or Epstein-Barr virus (EBV),
and usually results in prolonged cold and flu symptoms, swollen
lymph nodes, and fatigue. In 1981 a group of researchers looked
at CD4 and CD8 counts in ten consecutive patients with acute CMV
mononucleosis, and compared their counts with those of ten healthy
volunteers (Carney et al. 1981). The CD4 counts in people with mononucleosis
were significantly reduced, with the healthy volunteers having 73%
more CD4+ cells per ml than did people with mono, on average. The
CD8 cells in people with mono were increased, and the combination
of lower CD4 counts and elevated CD8 counts resulted in an inverted
CD4/CD8 ratio in every patient. The average ratio was only 0.2,
compared to the normal average of 1.7 found in controls. The CD4
counts were measured in nine of the ten patients, with the lowest
CD4 counts being 194, 202, and 255. The authors also found that
the T-lymphocytes of people with mononucleosis responded poorly
to antigens, showing depressed function. This paper was published
three years before HIV was first claimed to be the cause of AIDS.
Five years later, a different set of researchers measured various
lymphocyte subsets in acute EBV mononucleosis (Junker et al. 1986).
They took 17 consecutive patients who had recently been diagnosed,
gave them an immunization designed to activate their B lymphocytes,
and then took samples of blood. The immunization makes this study
different from any of the other studies to be examined here. They
did not find a statistically significant lowering of CD4 counts,
but they did find significantly lowered CD4/CD8 ratios due to elevated
numbers of CD8 cells, with the ratios falling below 1 as commonly
occurs in people diagnosed HIV-positive. They also found increased
B-cell activity with excess antibody production. Although this increased
antibody production is common in many of the conditions that cause
lowered CD4 counts, the authors assume that the increase occurs
because EBV infects lymphocytes. It appears more likely that increased
antibody production is a normal response to a wide variety of physical
and psychological stressors. The authors conclude that "these
studies demonstrate that infection with EBV affects both B and T
lymphocytes and causes a broad based transient immune deficiency
in patients with uncomplicated infectious mononucleosis" (Junker
et al. 1986, page 436). The immune deficiency was "transient"
but long lasting, with CD4/CD8 ratios gradually returning to normal
over the course of 4 to 6 weeks.
2d) Low CD4 counts in sepsis
In 1986, a group of researchers from Osaka, Japan published a study
in which they examined various lymphocyte subsets in 9 consecutive
patients admitted to the ICU with sepsis (Nishijima et al. 1986).
They examined their blood at weekly intervals for four weeks. The
CD4 counts in these patients were markedly reduced, with averages
beginning below 500 and staying there for the entire 4 week study
period. They also found T-cell function to be diminished, especially
in patients who did not survive, although there was no significant
difference in CD4 counts between those that died and those that
survived. The CD8 cells were also reduced in these patients, and
although in AIDS CD8 elevations are considered more typical, in
advanced AIDS cases the CD8 count can also be markedly reduced.
Because of the serious and life-threatening nature of sepsis, these
patients would be more similar to advanced AIDS, and so their immune
system profile is likely to be similar. The authors did not provide
individual CD4 counts, nor do they present data showing how many
patients have CD4 counts below 200, but having an average below
500 is still highly significant. Antiretroviral medications would
be started at this time if they had been diagnosed HIV-positive,
according to the most widely followed guidelines.
2e) Low CD4 counts in pulmonary tuberculosis
Tuberculosis is a relatively common infection in people diagnosed
HIV-positive, especially when compared to the general population.
It is also relatively common in other people who are immunosuppressed,
such as alcoholics, the homeless, intravenous drug users (IVDUs),
and people who suffer from malnutrition. In 1985 a group of researchers
in Indonesia examined the lymphocyte subsets in 26 patients newly
diagnosed with pulmonary tuberculosis (TB) (Beck et al. 1985). They
undertook the study because of a previous report of lowered CD4
counts in HIV-positive patients with TB in which the authors assumed
that the lowered CD4 counts were due to HIV. They found that in
HIV-negative TB patients CD4 counts were also significantly lowered
with an average of 748 compared to 1,043 in healthy controls. Because
the CD8 cells were slightly increased, they also found significantly
lowered CD4/CD8 ratios. Although the effects seen here were not
as dramatic as in the studies reviewed previously, with only 5 of
26 patients having CD4 counts less than 500, the authors still felt
their findings were highly significant to people diagnosed HIV-positive.
Here are some of their comments:
In a study of AIDS, ...Vieira et al. stated that it was possible,
but highly unlikely, that tuberculosis or its treatment could have
altered the relative numbers of circulating lymphocytes bearing
the markers CD4 ... and CD8, but they dismissed this possibility
because of the severity of the altered CD4/CD8 ratio... We now report
the relatively frequent occurrence of moderate CD4 lymphopenia in
patients with untreated but otherwise uncomplicated pulmonary TB."
(Beck et al. 1985, page 50)
The authors also comment on some similar findings in leprosy, as
well as in HIV-negative hemophiliacs:
“Moderate reduction in the CD4/CD8 ratio has been reported
in lepromatous leprosy, which reverts to normal under effective
chemotherapy... It is tempting to speculate that these changes are
analogous to those we now report in tuberculosis and that they are
a consequence of ongoing immune response to the disease... Interestingly,
comparable CD4 lymphopenia has been reported in hemophiliacs treated
with factor VIII, from a population apparently free from AIDS, and
this change has been attributed to a reaction to transfusion of
foreign proteins. (Beck et al. 1985, page 53).”
The reports of the effects of factor VIII transfusions on CD4 counts
have since been confirmed, as will be presented in section 3.
2f) Nearly all viruses interfere with lymphocyte function
In 1987 a summary article appeared in the Annual Review of Immunology
entitled simply, "Viruses Perturb Lymphocyte Functions"
(McChesney & Oldstone 1987). This article did not look at CD4
counts, but rather focused on the ability of CD4+ T-cells and other
cells to proliferate when presented with an antigen. The authors
reviewed evidence that a multitude of viruses interfere with the
ability of CD4+ T-cells to proliferate. Following are some quotes
from the text:
“Viruses with every type of genomic nucleic acid, encompassing
divergent replication strategies, are now known to infect lymphocytes.
The list (Table 1) of viruses that infect lymphocytes is not comprehensive,
but rather indicates representative viruses from different taxonomic
groups. With few exceptions, immunologic dysfunction has been associated
with the infections (McChesney & Oldstone 1987, pages 280-281).”
The viruses listed in Table 1 that infect human lymphocytes are
hepatitis B virus, group c adenoviruses, herpes simplex viruses,
cytomegalovirus, measles, mumps, respiratory syncytial virus (RSV),
vesicular stomatitis virus, influenza A, parainfluenza, rubella,
poliovirus, lymphocytic choriomeningitis virus, and human T-cell
leukemia viruses I and II.
After a lengthy section focusing on the measles virus, they go on
to discuss the class of viruses to which HIV belongs, retroviruses:
“Retroviruses of murine (mouse), avian (bird), feline (cat),
and human origin are immunosuppressive as well as oncogenic in their
hosts. The evidence of depressed cellular and humoral immune responses...
is independent of the transforming function of the virus... There
is no interspecies restriction, i.e. both murine and feline retroviruses
can suppress mouse and human lymphocyte proliferation in vitro (McChesney
& Oldstone 1987, page 287).”
The authors go on to describe that it is not necessary for the entire
retrovirus to be introduced, but only some of its proteins, meaning
that the depressed response is apparently a passive one that does
not require any action on the part of the viruses being discussed.
“A partially purified 15-kd structural protein of a feline
retrovirus inhibited the proliferation of feline lymphocytes...
The inhibition was dose dependent and occurred when the protein
was added as late as day 3 of a 4-day culture. In contrast, another
structural protein, p27, was not inhibitory (McChesney & Oldstone
1987, page 287).”
Unfortunately, at least for the purposes of this paper, the authors
do not discuss CD4 cells specifically.
3) Low CD4 counts caused by injections of foreign proteins
3a) CD4 irregularities in hemophilia
Hemophiliacs were one of the original HIV risk groups. As mentioned
above, hemophiliacs who are HIV-negative have been found to have
lowered CD4 counts as well as lowered CD4/CD8 ratios, and it appears
that this effect is caused by injections of Factor VIII. Antonaci
et al (1988) for example, found decreased CD4/CD8 ratios as well
as impaired CD4 function in HIV-negative hemophiliacs, stating in
their conclusion that "our findings clearly indicate an impairment
of immune function in hemophiliacs regardless of HIV infection"
(page 318). Similarly, Madhok et al. (1986) found depressed cell-mediated
immunity that was independent of HIV status. Their abstract contains
the following comments:
“There was no difference in skin response between patients
positive and negative for the human immunodeficiency virus (HIV).
In the whole group, and in seronegative patients (n = 17), there
was an inverse relation between exposure to clotting factor and
skin response. In seropositive patients (n = 12) no such association
was apparent. This study shows that clotting factor concentrate
impairs the cell mediated immune response to a new antigen in the
absence of infection with HIV (Madhok et al. 1986, page 978).”
3b) CD4 irregularities caused by injected drugs
Intravenous drug users (IVDUs) are another group with a high risk
of being diagnosed HIV-positive. In an article published in 1987
in the journal AIDS, lymphocytes were found to be reduced in HIV-positive
injection drug users as a direct function of how many injections
they received (Des Jarlais et al. 1987). The authors comment in
“Continued drug injection was associated with the rate of
CD4 cell loss... While it is not possible to distinguish the mechanism
underlying the relationship between continued drug injection and
CD4 cell loss, seropositive IV drug users should be warned that
continued injections may lead to increased HIV-related immunosuppression
(Des Jarlais et al. 1987, page 105).”
A similar finding in 1991, also published in the journal AIDS, found
that lymphocyte reactivity was much more significantly reduced in
IVDUs who injected more frequently, regardless of whether or not
they were HIV-positive (Mientjes et al. 1991). Although the CD4
cell function was impaired, no difference was found in CD4 counts
due to frequent injecting. They did find that HIV-positive IVDUs
had lower CD4 counts than did HIV-negative IVDUs, however. The T-cell
reactivity was 40-50% lower in IVDUs who were injecting 3 times
a day for the preceding several months when compared to a similar
group who had not injected in the preceding months, regardless of
their HIV status. The authors write: "We conclude that lymphocyte
reactivity is depressed by frequent injecting in both HIV-negative
and HIV-positive drug users (Mientjes et al. 1991, page 35).”
As far back as 1980, a report in the Journal of Immunology documented
lowered T-lymphocytes in IVDUs from Georgia, Illinois, and Massachusetts
(McDonough et al. 1980). The authors found that IVDUs in their study
had about half to one third as many T-lymphocytes, expressed as
a percentage, as control populations. Although they did not look
specifically at CD4+ T-lymphocytes, it has been found that when
total T-lymphocytes are reduced, CD4 counts are also normally reduced
(Kotze 1998). They discuss previous findings of opiate receptor
sites on T-lymphocytes, suggesting that the IV opiates were the
cause of the lowered T-cells, but they also recognize other possible
“Since most street heroin addiction involves polydrug use
including chronic use of marijuana, barbiturates, hallucinogens,
and other illicit substances, the hypothesis can be proposed that
the depression of T-lymphocyte percentage was caused by another
drug or combination of drugs, or by the effect of drug use on the
addict's general physical health and nutrition, i.e., the addict
milieu (McDonough et al. 1980, page 2542).”
The finding that a wide variety of physical and psychological stressors
can lower CD4 counts supports this multifactorial argument, in which
general health and nutrition can be significant contributing factors.
Finally, a review paper that was published in 1995 in the journal
Immunopharmacology, had an interesting discussion of the significance
of this information for IVDUs diagnosed HIV-positive:
“Among the unwarranted side effects of respiratory depression,
constipation, and physical dependence are the immunosuppressive
qualities, particularly those which affect cell-mediated immunity.
The immunosuppressive characteristics of opioid narcotics (e.g.,
morphine) have recently come into focus with the advent of acquired
immune deficiency syndrome (AIDS) and the putative causative agent,
human immunodeficiency virus type 1 (HIV-1). Specifically, a vast
reservoir of HIV-1-infected individuals exists among drug abusers.
Moreover, experimental evidence would suggest narcotic opioids may
increase viral load in infected individuals (Carr et al 1995, page
3c) CD4 irregularities caused by in utero exposure to opiates
In 1987, a study found that infants exposed to intravenous drugs
in utero also have decreased CD4/CD8 ratios and reduced CD4 function,
even when they are HIV-negative (Culver et al 1987):
“The CD4/CD8 ratio decreased with age in the drug-exposed
infants compared with control infants (P less than 0.005). ... Our
data demonstrate that infants of intravenous drug-using mothers
have distinct immunologic differences at birth compared with non-drug-exposed
infants and that these persist throughout the first year of life.
The cause appears unrelated to intrauterine viral infection, suggesting
a direct toxic effect of the drugs on fetal immunologic development
(Culver et al. 1987, page 230).”
These results show that multifactorial causes of low CD4 counts
probably apply to all age groups, including newborns. This is especially
true in the United States and in Europe where most newborns who
are HIV-positive are born to women who use intravenous drugs. In
Africa, malnutrition and other infectious diseases are more likely
to contribute, as will be discussed.
4) Low CD4 counts caused by injuries and burns
Several studies over the years have looked at the effects of severe
injuries or burns on CD4 counts. An early report appeared in 1982,
in which the authors looked at the percentage of CD4 counts in 30
patients admitted to their hospital's burn center (Antonacci et
al. 1982). They found that the severity of the burns was directly
correlated with depressed CD4 percentages. Patients with greater
than 25% of their body covered with 3rd degree burns had the lowest
percentages on admission, 37%, as compared to normals who had 63%.
They found a similar pattern with the CD4/CD8 ratio, but do not
report on absolute CD4 counts.
In 1984, a group of researchers decided to look at lymphocyte subsets
in patients with multiple trauma who had no burns (O'Mahoney et
al. 1984). They examined the blood of 31 patients and compared their
lymphocyte profile to ten normal controls. The CD4/CD8 ratio was
significantly reduced and inverted, with an average of 0.96, compared
with 1.82 in controls. They also found reduced lymphocyte proliferation/blastogenesis
in response to antigen challenges. While their original report said
they found no difference in absolute CD4 counts, they report in
a postscript that they were mistaken in this regard: "In looking
back now at the data, we feel the CD4 population did change relative
to the CD8 population because of an absolute decrease in the number
of CD4 cells (O'Mahoney et al. 1984, page 875).” The CD8 cells
were slightly increased as is also seen in people diagnosed HIV-positive.
In 1985, a study was published by some of the same researchers that
looked at two groups of patients with severe injuries: a group of
25 patients with burns, and a group of 21 patients with non-thermal
injuries (O'Mahoney et al. 1985). Both groups had severely lowered
CD4 percentages, which persisted until 50 days post-injury when
the study was concluded. They also found that people with lower
CD4 percentages were more likely to develop sepsis. Here are some
of the author's comments:
“The most important abnormality appears to be a reduction
in CD4 positive cells in burn patients... A change in the ratio
of CD4 to CD8 positive cells soon after injury is due to a reduction
in CD4 positive cells, not an increase in CD8 positive cells (O'Mahoney
et al. 1985, page 584).”
“We believe that the more important abnormality in the patients
studied is a reduction in T-cell help - both in terms of the number
of circulating CD4 positive cells and a reduction in interleukin
2 production seen both in burn and non-thermal injury patients.
Interleukin 2 is produced by T-cells, especially CD4 positive cells,
and promotes their growth and stimulates clonal expansion of T-cell
subsets: it is thus crucial in the response to foreign antigen (O'Mahoney
et al. 1985, page 585).”
The final study to be reviewed looked at 20 consecutive patients
who had emergency surgery due to major trauma (Polk et al. 1986).
This was the only study of trauma victims where absolute numbers
of CD4 cells are given, which makes it more significant from the
perspective of this paper. Figure 7 shows that 6 of 20 (30%) patients
had CD4 counts below 200 cells/mm3, and 13 of 20 (65%) had counts
below 500. The authors state simply: "Total T-cells represent
what is interpreted as a normal and common response to injury...
All patients had low total lymphocyte counts on admission and exhibited
a further decline on day 3 (Polk et al. 1986, page 287).”
10 of the patients had major infections, and three had minor infections,
which may have also contributed to their extremely low CD4 counts.
This paper is distinctive in that it attempts to explain a mechanism
for the lowered CD4 counts, citing a study supporting the hypothesis
that increased cortisol levels are responsible for the decline,
and that increased cortisol is also a normal response to injury.
They also argue that the reduction in CD4+ lymphocytes probably
does not represent cell death, but rather redistribution out of
the bloodstream and into the tissues. The argument that cortisol
plays a key role in lowered CD4 counts will be encountered again
in the section on psychological stress.
5) Low CD4 counts in normal human pregnancy
Several studies have been published on CD4 counts during normal
pregnancy. Most recently, Burns et al. published a study in 1996,
in which they attempted to control for potentially confounding factors
like the increased blood volume that normally occurs in pregnancy.
They used CD4 percentages because of this variable, and determined
that "our CD4 cell findings for HIV-negative women are consistent
with the majority of prior studies, which demonstrate a decline
in CD4 levels during normal pregnancy (Burns et al. 1996, page 1465).”
They also found that HIV-positive women had a more severe decline
which did not correct post-partum as it did in HIV-negative women,
although they fail to take into account other factors that can cause
lowered CD4 counts. These include any infections that the women
may have experienced, the traumatic effects of C-sections which
are normally performed on HIV-positive women to prevent neonatal
transmission, or the potentially severe psychological stress of
worrying if their baby will also be HIV-positive, which can take
up to 18 months to determine.
In 1989 a study was published of normal pregnancy which found reduced
CD4 percentages in the 1st and 2nd trimester, as well as reduced
CD4/CD8 ratios in the 2nd trimester (Castilla et al. 1989). The
authors comment on previous studies looking at a variety of lymphocyte
changes during pregnancy, stating simply, "In these studies,
variation in the number and proportion of CD4+ lymphocytes is the
alteration most frequently reported (Castilla et al. 1989, page
104).” The percentage of CD8+ lymphocytes was unchanged. They
also claim that "we have accounted for all the presently known
factors that can alter the concentrations of T-cell subsets in blood"
(Castilla et al. 1989, page 104), but in fact they did not consider
any of the factors described in this paper, such as infections,
trauma, overexercising, normal daily variation, or psychological
stress. This demonstrates that even clinicians and researchers doing
studies that focus specifically on CD4 levels are often unaware
of how many different conditions cause low CD4 counts.
The final study to be reviewed here is an early one (Sridama et
al. 1982). These researchers found reduced absolute CD4 counts,
as well as reduced percentages of CD4+ T-cells in 76 women with
normal pregnancies. By the third trimester, the pregnant women had
an average of only 543 + 169 CD4+ T-cells, compared to 1073 + 441
in non-pregnant women who served as controls. Both the absolute
numbers and the percentages stayed low until several months post-partum,
and similar results were obtained for the CD4/CD8 ratio which was
also reduced. B-cells were increased which is compatible with the
increased antibody levels normally found in human pregnancy, and
which are also commonly seen in people diagnosed HIV-positive. This
is the only study found of normal pregnancy that provides data on
absolute CD4 counts, and the average of 543, with a standard deviation
of 169, which means that a relatively large percentage of these
women had levels lower than 500, the point at which antiretroviral
medications would be started in someone diagnosed HIV-positive.
6) Reduced CD4 counts from overexercising
Only one study will be discussed in detail here (Verde et al. 1992),
a controlled trial in which ten athletes were asked to over-train
for three weeks. Blood samples were taken immediately before starting,
at the end of the three weeks, and again three weeks after returning
to normal exercise. The researchers found steady declines in the
percentage of CD4+ T-cells, with the lowest amount occurring 3 weeks
after returning to a normal exercise schedule. The authors also
found reductions in the CD4/CD8 ratio although these had normalized
by the 3 week endpoint. Finally, the authors checked levels
before and 5 minutes after acute exercise, and again found reductions
in CD4 percentages and in CD4/CD8 ratios, although these normalized
by 30 minutes post-exercise. It is interesting that a stress as
simple as overexercising for three weeks could cause lowered CD4
counts, and that they did not correct for at least three more weeks
after returning to a normal exercise schedule.
Other studies have found increased infections in athletes, especially
during periods of heavy training or competition, which suggest the
presence of "clinically relevant immune suppression in well
trained athletes (Mackinnon 1997).”
7) Low CD4 counts in malnutrition
A number of studies have looked at the immunosuppression that results
from malnutrition. Like the other conditions covered in this paper,
malnutrition causes severe immunodeficiency with depletion of CD4+
T-cells and reduction of cell mediated immunity. One of the most
recent studies is from India where malnutrition is extremely common
(Hegde et al. 1999). The authors found that reduced CD4 counts were
a natural physiological effect of malnutrition, and comment that
both HIV and malnutrition lead to a state of anergy with failure
of cell-mediated immunity. They also point out that HIV usually
occurs in conjunction with several other stressors of the immune
system: "Micronutrient abnormalities, concomitant infections,
and genetic factors are some of the compounding co-factors which
further contribute to the deterioration of immune functions in AIDS
patients (Hegde et al. 1999, page 318).”
A review paper from the Journal of Nutrition in 1996 also compares
malnutrition and AIDS, saying that "Protein/energy malnutrition
or deficiencies of single nutrients that assist in nucleic acid
metabolism generally lead to atrophy of lymphoid tissues and dysfunctions
of cell mediated immunity (Beisel 1996, page 2611S).” The
author comments on a syndrome of immunosuppression caused by malnutrition
which is called "NAIDS", and states that it often occurs
in people diagnosed HIV-positive:
“Immunological dysfunctions associated with malnutrition have
been termed Nutritionally Acquired Immune Deficiency Syndromes (NAIDS).
Infants and small children are at great risk because they possess
only immature, inexperienced immune systems and very small protein
reserves. The combination of NAIDS and common childhood infections
is the leading cause of human mortality. NAIDS can generally be
corrected by appropriate nutritional rehabilitation, but from a
viewpoint highly important to this Workshop, AIDS and NAIDS are
intensely synergistic... Aggressive nutritional support for children
with HIV infections could delay, or lessen, the development of NAIDS
and avoidance of NAIDS would improve both quality and length of
life (Beisel 1996, page 2611S).”
Later in the paper they describe some of the immunological changes
and clinical courses often seen in malnutrition, which sound very
similar to AIDS:
“Generalized protein energy malnutrition causes widespread
atrophy of lymphoid tissues, especially in children. The thymus,
spleen, tonsils, and lymph nodes are all affected, with evidence
of atrophy being greatest in T-lymphocyte areas of these tissues.…”
“Malnutrition, in turn, leads to a variety of immune system
dysfunctions,” which allow infectious diseases to flourish.
These closely linked events can initiate a "downhill spiral"
or a "vicious cycle" that leads inexorably to death.
“Protein energy malnutrition causes a marked repression of
cell-mediated immunity and the function of T-lymphocytes. Malnourished
children show anergy with loss of delayed dermal hypersensitivity
reactions and a decrease or reversal of the CD4/CD8 cell ratio...
In contrast, B-lymphocyte numbers and functions appear to be maintained.
While existing antibody production is conserved or even increased
during malnutrition, antibody responses and antibody affinity are
impaired (Beisel 1996, page 2612S).”
The "downhill spiral" of opportunistic infections that
"lead inexorably to death" is particularly reminiscent
of a description of AIDS. Beisel also reviews similar effects of
deficiencies of specific nutrients, such as vitamin A and zinc:
“Deficiencies of single essential nutrients with important
roles in nucleic acid synthesis and metabolism appear to cause derangements
in immunological functions that are quite similar to those seen
in protein energy malnutrition ... Both vitamin A and zinc deficiencies
are characterized by lymphoid tissue atrophy and depressed cellular
immunity... (Beisel 1996, page 2613S).”
To provide an idea of how prevalent the problem of malnutrition
is worldwide, he points out that the combination of malnutrition
induced immunosuppression and childhood infections "is the
leading cause of human mortality, producing more than 10 million
deaths per year, i.e. over 25,000 deaths per day (Beisel 1996, page
Another review paper published one year later, in 1997, made similar
arguments about the significance of malnutrition in impairing immunity
(Chandra 1997). This is the only paper found that gives percentages
of CD4 cells, although absolute CD4 counts are still not provided.
Figure 3 shows that the percentage of CD4+ T-cells in normal well-nourished
children is about 45%, while the percentage in malnourished children
is only 25%. Chandra describes the immune system changes seen in
“Nutrition is a critical determinant of immune responses and
malnutrition the most common cause of immunodeficiency worldwide.
Work done in the past 25 years has confirmed that impaired immunity
is a critical adjunct factor in malnutrition-associated infections.
...lymphoid atrophy is a dramatic feature of protein energy malnutrition.
...delayed hypersensitivity cutaneous responses are markedly depressed.
It is not uncommon to have complete anergy to a battery of different
antigens. These changes are observed in moderate deficiencies as
well. The skin reactions are restored after appropriate nutritional
therapy for weeks or months. ...the proportion of helper T-lymphocytes
(CD4+ T-cells) is markedly decreased, and the ratio of CD4 to CD8
cells is significantly lower than in well-nourished control subjects
(Chandra 1997, page 460S-461S).”
From this review it is seen that not only are the CD4 percentages
markedly reduced (from 45% to 25%), but that it takes "weeks
or months" of nutritional therapy for the effects of malnourishment
to revert to normal.
The final article to be examined is also a review (Harbige 1996).
This paper mentions similar findings to the ones already discussed,
including lowered CD4+ lymphocytes, decreased T-cell function, and
anergy. It also mentions the increase in antibody levels which is
also seen in people diagnosed HIV-positive, specifically serum IgG,
IgM, IgA, and IgD. In contrast to serum IgA, however, secretory
IgA is diminished. The main addition that this paper provides is
the mention of specific infections that are particularly common
in people who are malnourished:
“Among the many infectious organisms commonly associated with
protein energy malnutrition are Paramyxovirus (Measles), Rotaviruses,
Mycobacterium tuberculosis, E-coli, Shigella, E-histolytica, and
Pneumocystis carinii (Harbige 1996, page 289).”
Two of these organisms, M. tuberculosis and Pneumocyctis Carinii,
result in the diagnosis of AIDS when they occur in someone diagnosed
HIV-positive. Pneumocystis carinii pneumonia ("PCP") is
perhaps the single infection most commonly associated with AIDS
in the United States and Europe, while tuberculosis has always been
very common in Africa, and is today considered by some to be a common
"AIDS defining" illness there.
This information concerning malnutrition-induced immunodeficiency
and opportunistic infections is obviously significant for Africa,
where malnourishment is common and where HIV is also thought to
be the most prevalent, but it also may be very significant for people
in the United States and Europe. Several articles point to malnourishment
as a very common problem in AIDS due to decreased nutrient intake
or malabsorption (Babameto & Kotler 1997, Keusch & Thea
1993). These problems with nutrient intake can be caused by infections
of the oral cavity and gastrointestinal tract, which are quite common
in people diagnosed with AIDS. Antiretroviral medications, which
cause diarrhea and/or vomiting in well over half of the people who
take them, also have the potential to interfere significantly with
nutrient intake. In addition, decreased appetite is one of the standard
symptoms of depression which is common in people diagnosed HIV-positive.
Many years ago a "giving-in-giving-up" complex was described
that can result in people becoming ill and dying before their disease
has progressed. A disease like AIDS, with the hopeless description
provided to people diagnosed HIV-positive together with the the
social stigma that accompanies it, could be particularly susceptible
to this phenomenon (Engle 1968). Here are some quotes from a review
that focuses on malnutrition in HIV and AIDS which was published
in Gastroenterology Clinics of North America in 1997:
“Malnutrition is a common complication of HIV infection and
plays a significant and independent role in its morbidity and mortality.
Malnutrition was one of the earliest complications of AIDS to be
recognized, and unexplained weight loss is one of the most common
initial AIDS defining diagnoses to be given to people who were previously
“The development of malnutrition in clinical disease generally
is believed to be secondary to the underlying disease, and improvement
is believed possible only by addressing the underlying disease.
Studies have shown, however, that the effects of malnutrition in
HIV/AIDS are independent of immune dysfunction per se....
“Malnutrition associated with HIV infection has far reaching
ramifications... Many patients become too debilitated to work steadily
and come to rely on public or other assistance. Weight loss is often
the initiating event in a vicious cycle of increased fatigue and
decreased physical activity, including the ability to prepare and
consume food (Babameto & Kotler 1997, pages 393-394).”
The authors do not comment on the emotional burden of HIV/AIDS or
how this burden may reduce the person's appetite significantly,
which could add strength to the "vicious cycle" described
above. Finally, infections of any type put a physical stress on
the system which results in loss of weight (Scrimshaw & San
Giovanni 1997). This is because people break down their own tissues
to use as fuel, resulting in increased nutrient requirements. A
review article that examined this issue states:
“Infections, no matter how mild, have adverse effects on nutritional
status. The significance of these effects depends on the previous
nutritional status of the individual, the nature and duration of
the infection, and the diet during the recovery period [all of these
factors are often adversely affected in people diagnosed HIV-positive].
Conversely, almost any nutrient deficiency, if sufficiently severe,
will impair resistance to infection (Scrimshaw & SanGiovanni
Based on the articles examined above, it could easily be argued
that food, social support, and financial independence are solutions
that should be given a much higher priority when offering aid to
poorer nations. They also suggest that food, financial independence,
and social support should be a much higher priority for HIV and
AIDS programs in wealthy nations, as well.
8) Daily variation of CD4 counts
Only one study concerning the daily (diurnal) variation in CD4 counts
compared the diurnal variation in HIV-positive and HIV-negative
people, finding a significant variance in both (Malone et al. 1990).
They found that greater variations occurred in HIV-negative people,
but that both groups followed a pattern that coincides with known
daily fluctuations of cortisol, with minimum CD4 levels occuring
between 8:00 and 10:00 a.m., and maximums occuring at around 10:00
p.m.. Cortisol has a daily variation with maximums at about 8:00
a.m., and, as will be reviewed later in this paper, cortisol also
causes low CD4 and total T-lymphocyte counts. People with lower
baseline CD4 counts had much less diurnal variation. A flattening
of the normal diurnal variation of cortisol, together with elevated
average cortisol levels, is often seen in people under chronic psychological
stress, and is also common in people diagnosed HIV positive. Babameto
& Kotler (1997) state simply: "Endocrine alterations in
HIV infection include elevations in serum cortisol and loss of the
normal diurnal periodicity (page 401).” They do not comment
on the causes of these altered cortisol levels but chronic psychological
stress is a possibility given the stress associated with being diagnosed
HIV-positive or diagnosed with AIDS.
Malone et al.'s study of CD4 variation found that HIV-negative people
had an average variation of 506 cells/mm3 each day, while HIV-positive
people had only about 60 cells/mm3 of variation. The authors caution
that even this blunted variation is significant, however, stating
"3 of 12 HIV-positive patients had CD4+ cell counts below 200
cells/mm3 in the morning but had greater than 200 cells/mm3 in the
afternoon" (Malone et al. 1990, page 150). In other words,
in the morning they would be diagnosed with AIDS, but if their blood
was checked in the afternoon they would just be HIV-positive, albeit
with a relatively low CD4 count. They found similar results for
total lymphocyte counts, but CD4/CD8 ratios did not have statistically
significant changes. The authors conclude that blood draws for CD4
counts should always be done at the same time of day, but they do
not comment on relations between the diurnal cycle they observed
and the diurnal variation in cortisol.
9) Changes in CD4 counts and lymphocyte function due to psychological
stress and social isolation
A large number of studies have looked at the effects of stress on
the immune system, and several reviews have been published on this
topic (Bonneau 1993, Castle 1995, Herbert 1993, Kennedy 1988, Kiecolt-Glaser
1984, 1991, 1992 Laudenslager 1983, Pariante 1997, Stefanski 1998).
These studies have looked at people under chronic stress, such as
people suffering from depression; people who were recently divorced
or separated; college students during exams; and people who are
the primary caregivers of demented family members. There are also
a number of studies of animals under stress. Stress causes a state
of immunodeficiency characterized by a reduction of the number of
T-lymphocytes, with special targeting of CD4 helper T cells. There
is also a reduced CD4/CD8 ratio, with a relative increase in CD8,
suppressor/cytotoxic T cells. Unfortunately for the purposes of
this paper, the vast majority of studies look at lymphocyte function
and total T-cell counts. The few studies that have looked at CD4
cells used percentages (Kiecolt-Glaser et al. 1992).
A group of researchers led by Robert Sapolsky has done a great deal
of work observing the effects of psychological and social stress
on baboons and other primates, with most of their work focusing
on the neurotoxicity that is caused by stress, with dementia and
loss of neurons in the hippocampus (Sapolsky 1990, 1996). In one
study, however, they measured total lymphocyte counts and cortisol
levels in a group of baboons that were invaded by a highly aggressive
young male baboon whom they named Hobbs (Alberts et al. 1992). Hobbs
was particularly threatening to females in the group, and was apparently
attempting to use fear, physical intimidation, and abuse to increase
his chances of successful mating. Cortisol levels in the baboons
nearly doubled after Hobbs joined the group, with a slightly greater
increase among females. T-lymphocytes plummeted in the group from
a pre-Hobbs level of 67 per 10,000 red blood cells to a level of
about 39, a drop of 42%. When looking at only the levels in baboons
who were victims of Hobbs' aggression, the levels fell even more
steeply, to only 29 per 10,000 RBC's, a drop of 55%. Interestingly,
Hobbs himself had the lowest number of lymphocytes in the entire
group and the highest cortisol level, suggesting that his behavior
may have been taking an even greater toll on his system than it
did on the victims of his aggression. Field conditions prevented
them from determining the number of lymphocytes per microliter of
blood, or from specifically measuring CD4 cells, and the authors
comment on their use of lymphocyte counts instead of more sophisticated
“Whereas most studies of the effects of stress upon immunity
examine functional indices of immune competence (e.g. mitogen stimulation
tests, antibody generation, cytokine responsiveness), our field
conditions limited us to this rather crude quantitative measure
of numbers of cells (Alberts 1992 page 174).”
It is interesting that these researchers consider T-cell counting
to be a “crude measure” of immune competency. Although
the clinicians in this study could not report on CD4 counts, low
total lymphocyte counts are associated with low CD4 counts (Kotze
1998), so the findings of this study are likely to indicate that
CD4 counts are also lowered.
A review from as far back as 1988 also examined how the immune system
was affected by stress, with the following comments regarding CD4
helper T-cells (Kennedy et al. 1988):
“Data are given which document immunosuppressive effects of
commonplace, short-term stressors, as well as more prolonged stressors,
such as marital disruption and care-giving for a relative with Alzheimer's
disease. Immune changes included both quantitative and qualitative
changes in immune cells, including changes in herpes virus latency,
decreases in the percentages of T-helper lymphocytes and decreases
in the numbers and function of natural killer cells. These effects
occurred independently of changes in nutrition. Psychological variables,
including loneliness, attachment and depression were related to
the immune changes. The data are discussed in a framework in which
quality interpersonal relationships may serve to attenuate the adverse
immunological changes associated with psychological distress, and
may have consequences for disease susceptibility and health. (Kennedy
et al. 1988, page 77).”
Another review published in 1993 performed a meta-analysis of all
studies that looked at psychological stress and the immune system
(Herbert & Cohen 1993). In their discussion they mention their
findings regarding CD4, helper T-cells:
“In terms of cell numbers, stress is reliably associated with
a ... lower number of circulating B cells, helper cells, cytotoxic
cells, and large granular lymphocytes. Stress is also reliably associated
with a lower percent of lymphocytes that are T cells, helper T cells,
and cytotoxic T-cells (Herbert & Cohen 1993, page 373).”
The last review to be discussed here looked at short-term stressor
effects and made similar comments to the two reviews above, again
focusing on CD4 percentages instead of absolute CD4 counts:
“The immunological changes observed following short-term stressors
are very similar to those that have been described following epinephrine
injections: increased percentages of natural killer cells, decreased
blastogenesis in response to mitogens (decreased lymphocyte function),
and decreased percentages of CD4 cells. Total T cells and monocytes
did not change (Kiecolt-Glaser et al. 1992, page 680).”
This quote mentions epinephrine injections, but cortisol injections
also produce similar effects on the immune system. Secretion of
these hormones is the most commonly proposed mechanism for the immunosuppression
that occurs during states of acute or chronic psychological stress.
One of the major changes during times of stress is an outpouring
of the hormones epinephrine and cortisol which lead to a dramatic
reduction in the number of T-lymphocytes. The strength of the correlation
between decrease in T-cells and excess cortisol is so strong that
low T-cells is one of the diagnostic criteria for identifying excess
cortisol. Here are some quotes on this topic from a basic textbook
of physiology (Guyton 1996):
“Almost any type of physical or mental stress can lead within
minutes to greatly enhanced secretion of ACTH and consequently cortisol
as well, often increasing cortisol secretion as much as 20-fold
(Guyton 1996, p.966).
“Cortisol suppresses the immune system, causing lymphocyte
production to decrease markedly. The T lymphocytes are especially
suppressed. (Guyton 1996, p.964)
“Cortisol decreases the number of eosinophils and lymphocytes
in the blood; this effect begins within a few minutes of injection
of cortisol and becomes marked within a few hours. Indeed, a finding
of lymphocytopenia or eosinopenia is an important diagnostic criterion
for overproduction of cortisol by the adrenal gland. Likewise, the
administration of large doses of cortisol causes significant atrophy
of all the lymphoid tissue throughout the body... This occasionally
can lead to fulminating infection and death from diseases that would
otherwise not be lethal, such as fulminating tuberculosis in a person
whose disease had previously been arrested (Guyton 1996, p.965).”
It is interesting that this description of “fulminating infection
and death from diseases that would otherwise not be lethal”
sounds very similar to a description of AIDS. Cecil's Textbook of
Medicine also discusses the specific lowering of CD4 counts that
“A significant T lymphocytopenia occurs with a selective egress
from the circulation of CD4+ ‘helper-inducer’ T cells,
whereas CD8+ ‘cytotoxic-suppressor’ T cells are relatively
resistant to these effects. B lymphocytes are less susceptible to
glucocorticosteroid-induced effects than T cells, with little alteration
in intravascular number or composition. ...A variety of lymphocyte
functions, including activation, proliferation, and differentiation,
are sensitive to glucocorticosteroids. Although glucocorticosteroids
do not affect T-cell activation, down-regulation of RNA synthesis
decreases proliferation. ... Unlike T cells, B-lymphocyte function
is only modestly affected by glucocorticosteroids. Within 1 month
of glucocorticosteroid therapy, reduction in serum immunoglobulins
is noted because of increased catabolism. Antibody responses to
injected antigens are not impaired (Goldman 2000, page 111).”
This sounds exactly like what is described in AIDS with selective
lowering of CD4 counts, normal or increased CD8 counts, and normal
or increased antibody titers in the early stages. The similarity
is so striking that one cannot help but wonder if factors that increase
cortisol, such as chronic and severe psychological stress, could
be major players in the immunosuppression observed in AIDS. What
is even more curious, however, is that cortisol analogues are often
used in people diagnosed with AIDS to treat conditions such as pneumocystis
carinii pneumonia, a topic that will be discussed in the next section
(Immunosuppression caused by drugs used in the treatment of people
There is a disease which is characterized by long-term hypersecretion
of cortisol, called Cushing's syndrome or Cushing's disease. Cecil
Essentials of Medicine describes the physical manifestations of
Cushing's disease, many of which are also common in AIDS:
:Regardless of the etiology, hypercorticolism results in central
obesity, carbohydrate intolerance, muscle wasting, and osteoporosis.
Obesity is centripetal, manifested typically by a "buffalo
hump", increased supraclavicular fat pads, and moon faces.…
Depression occurs often, and rarely, patients may be frankly psychotic
(Andreoli et al. 1993).”
Muscle wasting, depression, and dementia-associated psychosis are
all relatively common findings in people diagnosed with AIDS. Cushing's
disease also causes immunodeficiency (Britton et al. 1975) and dementia
with loss of cortical neurons (Starkman et al. 1992), both of which
are characteristic of people diagnosed with AIDS. It is also interesting
that the redistribution of fat described here is a common side effect
seen in HIV-positive patients after long-term protease inhibitor
use, with the same "buffalo hump" and central obesity
which has been referred to as a "protease paunch". Early
osteoporosis has also been recently found to be another common adverse
effect of these medications.
Multiple studies have found that people diagnosed HIV positive have
chronically elevated cortisol levels, suggesting that the low CD4
T-cells in people diagnosed with AIDS could be at least partly caused
by elevated cortisol (Azar 1993, Christeff 1988, 1992, Coodley 1994,
Lewi 1995, Lortholary 1996, Membreno 1987, Norbiato 1996, Norbiato
1997, Verges 1989). It is important to note, however, that chronic
stress can induce immune suppression even when cortisol and epinephrine
are not elevated (Bonneau 1993, Keller 1983), indicaing that the
mechanisms by which stress affects health and immunity are not completely
In 1998, a group of researchers put the stress-cortisol hypothesis
to the test by checking CD4 counts and cortisol levels in people
who were randomly assigned either to a bereavement support group
intervention or to a wait-list control (Goodkin et al. 1998). The
intervention consisted of 10 weekly support group meetings, and
blood samples continued to be taken periodically for a total of
6 months. Some of the group members were HIV-positive, and the authors
stratified their data according to HIV status. They found that CD4
counts were increased in people receiving the support group intervention
as compared to controls, and that these increases correlated with
reduced levels of the stress hormone cortisol. Here is their description
of the results:
“In HIV-negative intervention subjects, the CD4 cell count
increased 112 cells/mm3, while that in HIV-negative control subjects
decreased 88 cells/mm3, for a difference of 200 cells/mm3 between
treatment and control groups. In treated HIV-positive individuals,
the CD4 cell count was stable, within laboratory error over the
entire six months. However, that in HIV-positive controls decreased
61 cells/mm3. Both [statistical tests] demonstrated a statistically
significant intervention effect on the CD4 cellcount (Goodkin et
al. 1998, page 387).”
Results like these may help to explain why socially isolated people
when compared to people with high levels of social support have
been found in over eight studies to have between double and triple
the death rates from all causes (Berkman 1979, House 1988, Ornish
1997). A recent study found that people diagnosed HIV positive were
two to three times more likely to “progress to AIDS”
if they were socially isolated and under high levels of stress (Leserman
et al. 1999). Here is a brief quote from the abstract of their paper:
“Faster progression to AIDS was associated with more cumulative
stressful life events (p<0.002), more cumulative depressive symptoms
(p<0.008), and less cumulative social support (p<0.0002).
...At 5.5 years, the probability of getting AIDS was about two to
three times as high on those above the median on stress or below
the median on social support... (Leserman et al., page 397).”
This study was not able to assess the impact of the stress of living
with the diagnosis HIV-positive nor can any study that is ethically
designed. It is not unreasonable, however, to infer that the stress
of the diagnosis is a strong contributor to immunosuppression in
people diagnosed HIV-positive, and even a contributor to mortality.
In addition to the cortisol hypothesis, another mechanism has been
presented in a paper in the journal Medical Hypothesis (Shallenberger
1998). The author presents a multifactorial model of AIDS in which
the immune system becomes overbalanced towards antibody-mediated
immunity (AMI) when it is chronically stressed. He does not feel
that HIV is necessary to create this imbalance, and cites similar
evidence to what has been cited here. When AMI becomes dominant,
the cytokines released by this arm of the immune system (interleukins
4 and 10) naturally suppress the other arm, called cell-mediated
immunity (CMI). CMI uses CD4+ cells in abundance, and when it is
suppressed the CD4 count will drop. If the AMI dominance is maintained
long enough it can become pathological and be very difficult to
reverse, eventually leading to failure of both AMI and CMI, according
to Shallenberger. His arguments are supported by the fact that people
who are diagnosed HIV-positive invariably have high levels of antibodies,
even when their CD4 counts have dropped significantly. Shallenberger
carefully documents that evidence of this phenomenon occurs in all
the risk groups for HIV whether or not they are HIV positive including
hemophiliacs, male homosexuals, IVDUs, and transfusion recipients.
This AMI dominance mechanism could still be mediated, at least in
part, by excess cortisol secretion, but the author does not discuss
the cortisol hypothesis in his paper.
10) Immunosuppression caused by drugs used in the treatment of people
Many drugs regularly used to treat people diagnosed HIV-positive
have severe immunosuppressive effects as well as other serious adverse
effects. These include corticosteroids, AZT, other drugs in the
same class as AZT, certain antibiotics, and protease inhibitors.
People diagnosed HIV-positive take these drugs indefinitely which
increases the risks of adverse effects significantly.
Corticosteroids, as described above, cause an immunosuppression
that is extremely similar to the immunosuppression that is claimed
to be caused by HIV, with lowered CD4 counts and sparing of CD8
cells as well as sparing of antibody production. In spite of this,
corticosteroids are commonly used in people diagnosed HIV-positive
to treat conditions like pneumocystis carinii pneumonia, as the
following quote from Cecil Textbook of Medicine demonstrates:
“The major breakthrough in the search for more effective therapies
for Pneumocystis has been the irrefutable evidence that mortality
for severe episodes can be reduced nearly twofold by use of corticosteroids
within 72 hours after beginning specific anti-Pneumocystis therapy
(Goldman 2000, page 1882).”
Thus corticosteroids have been found to reduce mortality from what
is perhaps the most common serious infection in people diagnosed
with AIDS, and at the same time they cause the exact same immunosuppression
that is supposedly allowing pneumocystis to flourish. This seeming
contradiction is very difficult to explain, at least if it is true
that low CD4 counts are truly the primary problem in people diagnosed
Other medications used to treat people diagnosed HIV-positive, such
as AZT and protease inhibitors, also have immunosuppressive effects.
AZT, also called Retrovir or zidovudine, continues to be the most
commonly used drug in people diagnosed HIV-positive. Up until 1996
it was used alone as a monotherapy and it was given at a dose that
is about triple the dose used today. In 1996 it began to be used
in combination with other drugs such as protease inhibitors and
the dose was reduced significantly. Many other drugs, including
ddI, ddC, 3TC and d4T, that are often used in combination with AZT
share the same basic mechanism as AZT and have similar toxicities.
The most severe effect of AZT is a lowering of the number of neutrophils,
which are the most numerous cells of the immune system, as well
as lowering eosinophils, basophils, red blood cells, and platelets.
The elimination of neutrophils, eosinophils, and basophils, which
are all critically important cells of the immune sytem, is called
"granulocytopenia.” If the number of neutrophils is lowered,
this is called "neutropenia.” If someone suffers from
granulocytopenia, they also by definition suffer from neutropenia.
Neutropenia and granulocytopenia are also common complications of
cancer chemotherapy. The clinical course of severe neutropenia,
as described in the basic pathology textbook Pathologic Basis of
Disease (Robbins et al. 1994), describes what happens to people
with severe neutropenia.
“CLINICAL COURSE: The symptoms and signs of neutropenias are
those of bacterial infections. ... In severe agranulocytosis with
virtual absence of neutrophils, these infections may become so overwhelming
as to cause death within a few days. (p.631).”
This sounds quite similar to a description of AIDS. Later stages
of HIV infection are often associated with neutropenia as well as
low CD4 counts. This may be why many of the AIDS defining diseases
are bacterial infections, which are not considered typical infections
in people suffering from low CD4 counts and a specific loss of cell-mediated
immunity. Robbins uses italics to highlight the following statement
about neutropenia: "the most severe forms of neutropenias are
produced by drugs" (Robbins et al 1994, page 630). This is
especially true when the drugs are given for long periods as is
typical in people diagnosed HIV-positive.
While AZT and other drugs used in combination therapy do not cause
low CD4 counts in the short term, it is probable that long term
use will also lower CD4 counts significantly, especially if it is
given for long periods. This finding has been ignored because the
original study of AZT's toxicity to CD4 lymphocytes claimed that
very high concentrations, much higher than concentrations used in
clinical practice, were needed before CD4+ lymphocytes were affected.
What is not mentioned in the Physician's Desk Reference is that
AZT has been found in five studies performed afterwards to be equally
toxic to CD4+ T lymphocytes. These later studies found that AZT
was toxic to CD4 lymphocytes at about the same dosage that is given
to people diagnosed HIV-positive (Duesberg 1992).
Glaxo Wellcome puts the following warning in bold-faced, capital
letters at the start of the section in the 1999 Physician's Desk
Reference that describes AZT.
“RETROVIR (ZIDOVUDINE) MAY BE ASSOCIATED WITH SEVERE HEMATOLOGIC
TOXICITY INCLUDING GRANULOCYTOPENIA AND SEVERE ANEMIA PARTICULARLY
IN PATIENTS WITH ADVANCED HIV DISEASE (SEE WARNINGS). PROLONGED
USE OF RETROVIR HAS ALSO BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY
SIMILAR TO THAT PRODUCED BY HUMAN IMMUNODEFICIENCY VIRUS. (PDR 1999).”
An earlier version of the Physician's Desk Reference, published
in 1992 made the connection even clearer:
“It is often difficult to distinguish adverse events possibly
associated with Zidovudine administration from underlying signs
of HIV disease or intercurrent illness (PDR 1992).”
Another strongly worded warning appears in the 1996 edition of the
United States Pharmacopeia's USP DI: Drug Information for the Health
“Because of the complexity of this disease state, it is often
difficult to differentiate between the manifestations of HIV infection
and the manifestations of zidovudine (AZT). In addition, very little
placebo controlled data is available to assess this difference (United
States 1996, pages 3032-3034).”
Granulocytopenia means a deficiency of the most numerous cells of
our immune system, which in turn leads to opportunistic infections
that can become "so overwhelming as to cause death within a
few days.” Thus, AZT, by its maker's own admission, can attack
a person's own immune system, which is the very thing that HIV is
In an article in the journal Nature Medicine in 1998, the author
argues that the initial rise in CD4 count after starting on antiretroviral
medications does not represent any decreased killing of CD4+ T lymphocytes,
but rather represents shifting of available cells out of the tissues
and into the bloodstream (Roederer 1998). The increased T-cell count
created by the use of AZT was shown to have no bearing on survival
in the best and most well-controlled study available on AZT, the
Concorde Study (1994). The Concorde study, originally published
in the New England Journal of Medicine in 1992, found that people
who were given AZT earlier died faster even thought their CD4 counts
were higher, although the difference in death rates were not statistically
significant (Henderson et al. 1992). Recent evidence shows that
AZT and several protease inhibitors specifically inhibit microbes
that commonly cause infections in people diagnosed HIV-positive.
Protease inhibitors, for example, inhibit Pneumocystis carinii and
Candida albicans, two of the most common infections found in people
diagnosed HIV-positive (Cassone 1999, Atzori 2000). AZT inhibits
many different strains of bacteria, including enterobacter, shigella,
salmonella, klebsiella, citrobacter, and e-coli, and AZT also acts
synergistically with commonly used antibiotics such as Bactrim (PDR
1999). Unfortunately, the antimicrobial effects may be short lived
as the following statement indicates: "Limited data suggests
that bacterial resistance to zidovudine (AZT) develops rapidly (PDR
1996, page 1158).” It is possible that these drugs may inhibit
many other microbes as well, but studies looking at their effects
on most microbes have not been done. The finding that they attack
microbes may explain the rises in CD4 counts that people on these
drugs experience in the short term since infections with these microbes
are associated with extremely low CD4 counts even in the absence
of HIV infection. As bacterial resistance develops in the microbes
and they again flourish, however, the CD4 count would naturally
begin to fall. It is also possible that the immunosuppressive effects
of long-term administration of anti-HIV medications could bring
the CD4 count down along with the other white cells.
An example of a study that documented the toxic effects of AZT on
healthy people's immune systems was published in the Annals of Hematology
in 1994 (Schmitz et al. 1994). AZT was given to 14 health care workers
who had been exposed to HIV-contaminated blood through needle sticks
and similar accidents. This type of study is important because the
toxicity observed cannot be blamed on HIV, as is quite likely to
happen in people diagnosed HIV-positive. None of the 14 workers
actually became HIV-positive as a result of their needle stick,
which is not surprising since the likelihood of contracting HIV
is estimated at about 1 in 333, which is even less than the probability
of finding someone who is HIV-positive when randomly picking from
the general population. Fully half of the 14 workers had to quit
the drug because of severe toxic effects, and the study was stopped
early because of these effects. Only 11 of the 14 people could continue
to take the drug for more than four weeks. Neutropenia developed
in 36% (4 of 11) of the people who completed 4 weeks of AZT treatment.
The three people who could not make it to four weeks dropped out
due to "severe subjective symptoms". What is truly remarkable
in this study is that these side effects developed in only 4 weeks,
while patients diagnosed HIV-positive often stay on AZT and other
similar drugs for years.
Other drugs commonly used with people diagnosed HIV-positive have
similar immunosuppressive effects. Didanosine (ddI or Videx) is
listed in the Physician's Desk Reference (1999) as causing granulocytopenia
in 25% of children who had normal values to begin with, and in 62%
of children whose values were already abnormal. In adults, 8% experienced
"serious" levels of granulocytopenia, compared to 15-19%
in patients treated with AZT. Perhaps more significantly, between
13% and 16% experienced serious levels of "leukopenia"
which involves reductions of all white blood cells including lymphocytes.
The most serious adverse effects of didanosine, as well as lamivudine
(3TC or Epivir), stavudine (d4T or Zerit), and zalcitabine (ddC
or Hivid) which are all in the same class of drugs as AZT, however,
are dose dependent peripheral neuropathy and pancreatitis. Although
these effects are unlikely to be blamed on HIV, pancreatitis is
a life threatening condition. In Phase 1 trials of didanosine, pancreatitis
occurred in 9% of people given doses in the range currently used,
and it occurred in 27% of people given higher doses. Peripheral
neuropathy was even more common, occurring in 51% of people on the
higher dose and 34% of people in the dose range commonly used today.
Finally, the drug used to treat and prevent CMV retinitis, gancyclovir,
has serious immunosuppressive effects, with a similar bold faced
warning in the PDR to what was seen in the section on AZT:
"THE CLINICAL TOXICITY OF (GANCICLOVIR) INCLUDES GRANULOCYTOPENIA,
ANEMIA, AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS
CARCINOGENIC, TERATOGENIC, AND CAUSED ASPERMATOGENESIS (page 2104).”
According to current treatment guidelines, gancyclovir is supposed
to be started in all people diagnosed HIV-positive if their CD4
counts fall below 100, or if they are diagnosed with CMV retinitis.
They are supposed to continue weekly injections of gancyclovir indefinitely,
until they die.
An article in the New England Journal of Medicine looked at the
muscle wasting (myopathy) which is caused by AZT, and compared it
to muscle wasting that has been presumed to be caused by HIV (Dalakas
et al. 1994). Their comments in the abstract indicate a major problem:
“We conclude that long-term therapy with Zidovudine can cause
a toxic mitochondrial myopathy, which... is indistinguishable from
the myopathy associated with primary HIV infection... (Dalakas et
al 1994, page 1098).”
Robbin's text on pathology also contains sections on mitochondrial
myopathy, stating that this kind of muscle wasting results in severe
weakness. Because it is also associated with neurological symptoms
such as dementia, according to Robbins, mitochondrial myopathies
"may also be classified as mitochondrial encephalomyopathies"
(Robbins et al. 1994, page 1290). Encephalomyopathy, in lay language,
means widespread damage to the brain and spinal cord.
Although most retrospective studies have not found AZT to be associated
with "HIV dementia”, retrospective studies are uncontrolled
and thus open to many confounding variables and biases. One of the
better controlled studies did find that "HIV dementia"
was twice as likely to happen in people taking AZT. In this study,
published in the journal Neurology (Bacellar et al 1994), the authors
:Among subjects with CD4+ cell counts < 200/mm3, the risk of
developing HIV dementia among those reporting any antiretroviral
use (AZT, ddI, ddC, or d4T) was 97% higher than among those not
using this antiretroviral therapy (page 1895).”
Because the authors include only people with low CD4 counts in their
comparison, it is less likely that people took AZT because they
were already sick. They go on to discuss peripheral neuropathy,
a degeneration of sensory nerves:
“In addition, the findings of our analysis seem to confirm
previous observation of a neurotoxic effect of antiretroviral agents.
Numerous studies have linked the use of ddI, ddC, and d4T to the
development of toxic sensory neuropathies, usually in a dose-response
fashion (page 1895).”
These studies are but a sample of the evidence that suggest that
AZT and other anti-HIV drugs used as monotherapy or as parts of
protease inhibitor cocktail regimens are causing a variety of AIDS-like
symptoms which are being blamed on HIV.
11) Unexplained low CD4 counts and "idiopathic CD4 T lymphopenia"
In 1992 the US Centers for Disease Control (CDC) in Atlanta introduced
a new condition characterized by unexplained low CD4 counts in the
absence of HIV infection. They called this syndrome "idiopathic
CD4 T lymphopenia" (ITL). Bird (1996) provides an excellent
summary of this condition which he calls "Non-HIV AIDS"
or "Non-HIV associated immunodeficiency.” He concludes
that it is distinct from HIV associated immunodeficiency, but he
overlooks a number of key points. Several of these points will be
reviewed in detail.
Although Bird (1996) does consider the effects of infections on
CD4 counts, he fails to take into account most of the conditions
reviewed in this paper, such as malnutrition, trauma, burns, intravenous
injections of foreign proteins, over-exercising, pregnancy, corticosteroid
use, normal daily variation, psychological stress and social isolation.
He also fails to point out that infections alone could easily explain
the low CD4 counts found in people diagnosed HIV-positive who often
experience chronic or recurring infections of various types. In
addition, malnutrition, injections of foreign proteins and chronic
severe psychological stress are all common in people diagnosed HIV-positive.
It appears that one of Bird's major purposes in writing his paper
was to refute the positions of several researchers who question
the significance of HIV in causing AIDS. These arguments were being
reinvigorated by the discovery of people with low CD4 counts who
were HIV negative. Following are the primary positions which Bird
attempts to refute:
1) AIDS is multifactorial with multiple causes. This has been argued
by many clinicians and researchers such as Joseph Sonnabend who
has been working with people diagnosed HIV-positive since before
HIV was first claimed to cause AIDS (Sonnabend 1984).
2) HIV needs cofactors to become active, a position advocated by
the discoverer of HIV, Luc Montagnier, and others (Grau 1998).
3) Other factors are the only significant ones, and HIV is an opportunistic
virus that does not cause AIDS or immunosuppression of any kind.
This stance is maintained by a number of prominent researchers including
Peter Duesberg, the retrovirologist who first mapped out the genetic
code of retroviruses, and David Rasnick who holds a number of patents
in protease inhibitor research (Duesberg & Rasnick 1998).
Although Bird's paper is thorough in many ways, he overlooks much
of the information presented above, and also contradicts itself
several times. In the beginning of his paper, he presents a description
of how the occurrence of "non-HIV AIDS" was first discovered
and made public:
“The unexpected announcement of the Eighth International AIDS
Conference, that the US CDC in Atlanta was investigating a series
of reported cases of AIDS in which HIV did not seem to be implicated,
rekindled many of these issues. At this conference the possibility
was discussed that many AIDS cases might not be caused by HIV (Bird
1996, pages 171-172).
“The majority of cases classified as non-HIV AIDS or CD4+
lymphopenia have been detected following investigation of clinical
signs which suggest cellular immunodeficiency. The patients have
presented with a history of severe or recurrent infections with
intracellular pathogens or virus-associated malignancies which,
even before the description of AIDS, were recognised as being highly
suggestive of underlying deficiency of cell-mediated immunity. Indeed,
it was this constellation of clinical features that clearly identified
a new clinical entity of AIDS (Bird 1996, page 173).”
After this comparison which reveals just how similar the two conditions
are, he goes on to make another admission regarding pneumocystis
“Indeed, pneumocystis carinii was first identified as a pathogen
amongst severely malnourished (and thus immunodeficient) populations
in continental Europe immediately following the Second World War
(Bird 1996, page 173).”
Bird does not mention that malnutrition is characterised by exactly
the same type of immunodeficiency seen in AIDS, with low CD4 counts,
increased immunoglobulins, and severely depressed cell-mediated
immunity. He also does not mention how common malnutrition is in
people diagnosed HIV-positive (Babameto & Kotler 1997, Keusch
& Thea 1993). After these assertions describing the similarities
between non-HIV associated immunodeficiency and AIDS, he makes several
statements in an attempt to distinguish the two.
First, he states that "the condition [of non-HIV associated
immunodeficiency] remains exceptionally rare" (Bird 1996, page
176). Even considering only malnutrition, which has a state of immunodeficiency
that is very similar to what is seen in AIDS, this statement appears
questionable. Asoutlined above, malnutrition is the leading cause
of immunodeficiency worldwide, can be caused by repeated infections,
and is very common in people diagnosed with AIDS regardless of their
financial status. Other conditions that are associated with very
low CD4 counts, such as sepsis, pneumonia, and mononucleosis, are
also quite common. Sepsis causes over 100,000 deaths per year in
the United States alone, affects young and old alike, and is characterized
by markedly lowered absolute CD4 counts, as outlined previously.
Another statement that attempts to distinguish between non-HIV AIDS
and HIV-induced AIDS is that "most non-HIV immunodeficiency
cases have normal or low immunoglobulin levels and also have low
CD8 counts" (Bird 1996, page 175). Nearly all of the conditions
outlined above were characterized by lowered or inverted CD4/CD8
ratios, showing that CD8+ T-cells at the very least are affected
much less than CD4 cells. In many of the conditions discussed above,
especially infections, CD8+ T-cells are usually either significantly
elevated or normal. Bird himself admits this later in his paper:
“Low CD4 counts have been reported as a transient or long-lasting
feature of a number of acute and chronic infectious diseases.
However, in most cases the effect is to lower the percentage of
CD4+ cells as a result of increased CD8 cells, rather than as a
consequence of absolute reduction of CD4 cells (Bird 1996, page
Here he not only admits that CD8 cells are often elevated in a wide
variety of common human infections, but also makes another serious
misstatement regarding CD4 counts. The studies reviewed in this
paper clearly show that absolute numbers of CD4+ T-cells are commonly
reduced in various human infections, often severely so, in spite
of Bird's claim to the contrary. While it is true that CD8 counts
were reduced in septic patients, this reduction is often seen in
very advanced stages of AIDS, and sepsis is an extremely serious
condition which is more comparable to advanced stages of AIDS than
it is to earlier stages. Although most studies reviewed did not
discuss immunoglobulin/antibody levels, which Bird says are "low
or normal" in non-HIV AIDS, malnutrition, which is perhaps
the most common condition that occurs in people diagnosed with AIDS,
is characterized by increased antibody levels, as described previously.
Bird also does not consider that in late stages of AIDS a complete
immune collapse is often seen, with lowered CD4, CD8, and immunoglobulin
levels, so the use of these parameters to attempt to distinguish
non-HIV and HIV acquired immunodeficiency is not particularly reliable.
Bird also states "whereas some cases [of non-HIV associated
immunodeficiency] have had a fulminant and fatal outcome, others
have been associated with longer term survival associated with stabilisation
or reversal of the immunodeficiency (page 175).” Even if a
minority of people with non-HIV associated immunodeficiency experience
a "fulminant and fatal outcome,” this is enough to suggest
that possible causes of this outcome should be carefully studied.
The information obtained from such a study has the potential to
provide a great deal of help to people diagnosed HIV-positive, especially
considering the studies reviewed above which show how common the
conditions associated with low CD4 counts are in this population.
Even Bird's stance that "longer term survival" somehow
distinguishes them is questionable, however. Long term survival
and reversals of CD4 counts are also very common in people diagnosed
HIV-positive, although people with progressive downhill courses
have received more attention. The average time between a diagnosis
of HIV-positive and diagnosis of AIDS is estimated at about ten
years, which was based on studies conducted when an opportunistic
infection had to be present to diagnose AIDS, i.e. low CD4 counts
could not be used for the diagnosis. Between 5 and 15% of people
diagnosed HIV-positive never even show immunological abnormalities
(Learmont et al. 1992, Ashton et al. 1998, Walton 1999). Finally,
at the time of Bird's writing (1996), non-HIV AIDS had only been
recently discovered so the potential for a long term outcome could
not be determined accurately. Protracted courses with increases
and decreases of CD4 counts have always been a common occurrence,
even before the introduction of protease inhibitors.
Another statement of Bird's attempts to explain why non-HIV associated
immunodeficiency was clustered around AIDS risk groups:
“Although groups at risk of HIV infection appear to be over-represented
amongst the early case reports, these almost certainly represent
an ascertainment bias. ... Many of these cases, had they occurred
in the general population, might otherwise have escaped detection
(Bird 1996, page 176).”
The problem with this line of reasoning is that it also applies
equally well to HIV and AIDS, because HIV tests were only routinely
given to people in the identified risk groups. It is likely that
a very high percentage of people who die of sepsis, multiple trauma,
pneumonia, tuberculosis, and malnutrition would qualify for a diagnosis
of AIDS based on their clinical and immunologic picture. Indeed,
the only obvious difference between them is the result that they
have on the HIV antibody tests. Thus a similar ascertainment bias
appears to be present in the exclusive focus on HIV. The same problem
exists with Bird's next point regarding non-HIV associated immunodeficiency:
“The other issue that needs to be considered is whether the
low CD4 counts reported in individual patients could be secondary
to their particular infections rather than responsible for them
(Bird 1996, page 177).”
The problem here is that people diagnosed HIV-positive are even
more likely than others to have lowered CD4 counts "secondary
to their individual infections,” so this is a very poor distinguishing
feature. In Bird's own words, as cited previously, "The patients
[with non-HIV AIDS] have presented with a history of severe or recurrent
infections... which, even before the description of AIDS, were recognised
as being highly suggestive of underlying deficiency of cell-mediated
immunity. Indeed, it was this constellation of clinical features...
that clearly identified a new clinical entity of AIDS (Bird 1996,
page 173).” In fact the very definition of AIDS according
to the CDC includes the presence of any one of about 25 different
infections in someone previously diagnosed HIV-positive (Goldman
2000). Recurrent infections, especially if other conditions such
as severe psychological stress are present, could result in a lowered
CD4 count that may stay low indefinitely. The fact that Bird overlooks
this possibility is even more unusual because he later admits that
low CD4 counts can be long-lasting even from a single infection:
“Since CD4 depletion in the blood [after an infection] can
persist for long periods, the current CDC definition [of idiopathic
CD4 T lymphopenia] is unsatisfactory. I propose that a period of
at least 6 months is added to the requirement for consecutive low
CD4 counts to rule out short-term secondary effects of infection
(Bird 1996, page 177).”
While a six month waiting period would certainly be an improvement,
it does not address the possibility that a person could easily suffer
another infection within the six month follow-up period, especially
if they are prone to recurrent infections. In addition, Bird fails
to take into account any of the non-infectious conditions associated
with low CD4 counts which are also quite common. In summary, all
of the distinctions Bird attempts to make between non-HIV AIDS and
HIV associated AIDS are either weak or nonexistent which leaves
open the possibility that non-HIV AIDS and HIV associated AIDS can
be caused by the same factors. Identifying and helping people overcome
these non-HIV factors could be more effective than the current practice
which focuses solely on trying to eliminate HIV.
Bird also introduces another aspect of CD4 counting which may explain
why people initially believed that the low CD4 counts found in people
diagnosed HIV positive were a new and unique entity. He points out
that the tests used to measure CD4 counts were developed at about
the same time as AIDScases were first being identified. This meant
that researchers did not know much about CD4 counts, nor did they
know that most of the conditions being used to diagnose people with
AIDS, such as severe and chronic infections, are strongly associated
with low CD4 counts, as are many other conditions that they were
“Sporadic cases of apparent late-onset cellular immunodeficiency,
associated with opportunistic infections, have appeared as case
reports over the years. Because the emergence of HIV-associated
AIDS coincided with the introduction of T-cell specific monoclonal
antibodies which permitted the identification and quantitation of
human CD4-positive T lymphocytes, no T-lymphocyte surface marker
results are available on many of the earlier cases (Bird 1996, page
“Individual T-cell populations could not be quantified before
1978 (Bird 1996, page 173).”
The first AIDS cases were identified in 1979, together with the
extremely low CD4 counts that were thought to be the cause of their
chronic infections. Because the tests used to measure CD4 counts
were only developed the year before, in 1978, it is very likely
that the assumption that HIV was causing the death of CD4 cells
was made prematurely, before any clinicians or researchers had enough
experience or knowledge about CD4 counts to make accurate decisions
about their significance. Studies since that time on low CD4 counts
have been widely ignored unless they focused on people diagnosed
HIV-positive, creating the illusion that low CD4 counts are somehow
specific to HIV and AIDS. This illusion may have allowed HIV to
be falsely credited with creating immunodeficiency while other factors
that are more significant are being ignored.
This review is extremely limited in scope, and many of the studies
presented here use different measures of immune function making
it difficult to perform accurate comparisons. Nevertheless, it is
remarkable that so many different conditions are associated with
profoundly reduced CD4 counts, as well as reduced CD4 percentages,
reduced measures of lymphocyte function, and reduced CD4/CD8 ratios.
The fact that HIV-negative people with many common conditions like
mononucleosis, pregnancy, and pneumonia can have CD4 levels below
those needed to diagnose AIDS suggests that the common use of CD4
counts to make diagnostic and treatment decisions should be carefully
reappraised, especially since most clinicians are apparently unaware
of how serious these influences are. It is also apparent that the
syndrome of AIDS, with extremely low CD4 counts and severe or fatal
infections, is fairly common in people diagnosed HIV-negative, and
is likely to be present in between 40 and 70 percent of people admitted
to intensive care units with severe acute or chronic infections
(Feeney et al 1995, Williams et al. 1983). In people who die of
their infections, this percentage may be even higher.
Low CD4 counts and other immunosuppressive effects are associated
with so many different physical and psychological stressors that
it is possible that these other factors are the primary ones causing
immunosuppression in many people diagnosed HIV-positive. Following
is a brief list of factors commonly present in "high-risk"
groups that could explain or contribute to a low CD4 count:
1) In Africa, malnutrition, a variety of endemic infectious diseases,
psychological stress, and social ostracism could all be strong factors
in causing an acquired immunodeficiency.
2) In the United States and Europe, AIDS is still primarily confined
to the original risk groups, male homosexuals, IV drug users, and
hemophiliacs, all of whom regularly experience many of the conditions
a) Male homosexuals suffer from societal rejection which causes
psychological stress and social isolation. When AIDS first appeared,
several events had made the social isolation of male homosexuals
painfully clear; a successful campaign to repeal gay rights in Miami
Dade County was being led by Anita Bryant, and the first elected
official in the United States who was openly gay, Harvey Milk, was
assassinated. Ironically, over the years the phenomenon of AIDS
may have helped significantly to reduce this social ostracism and
hatred, albeit in the context of a widespread human tragedy.
b) The small subset of gay men in whom AIDS first appeared were
engaging in a type of party atmosphere which involved multiple partners
[200 per year on average], late nights, and the regular use of alcohol,
recreational and pharmaceutical drugs. Many people in this group
suffered from recurrent or chronic sexually transmitted diseases,
parasitic infections and malnutrition as well as general ill health.
c) IV drug users live in conditions of psychological stress and
social isolation, and also often suffer from malnutrition. Injections
of foreign proteins are a daily routine, and opiates have also been
shown to cause immunosuppression. IV drug users have always had
high rates of infectious diseases including cellulitis, tuberculosis,
pneumonia, and non-healing ulcers.
d) Hemophiliacs need regular transfusions of Factor VIII, which
introduces a number of foreign proteins and impurities into their
bloodstream. The quality of the Factor VIII has steadily improved
over the years, as has the health and life expectancy of hemophiliacs,
but in spite of this they still have chronic health problems and
their life expectancy is still greatly reduced when compared to
the normal population.
e) Corticosteroids, which are cortisol analogues, are often used
as treatments in people diagnosed HIV-positive, especially in Western
nations, for illnesses such as pneumocystis carinii pneumonia (PCP).
3) The very diagnosis of HIV-positive carries a substantial burden
of psychological stress and social isolation which is made even
worse when the CD4 count is found to be reduced, or when "full
blown" AIDS is diagnosed.
It would be helpful to see studies of CD4 counts in even more common
illnesses like influenza, and to see studies that try to determine
when the CD4 counts begin to fall. If the CD4 counts were low before
experiencing the conditions presented, the CD4 count could have
caused the condition. The low counts in burn and trauma victims,
however, argue in favor of the hypothesis that the conditions themselves
caused the low CD4 counts, as it is difficult to argue that such
a high percentage of people had low CD4 counts before the trauma
was experienced. The studies reviewed here show that the CD4 counts
can stay low for weeks or months and this effect would be magnified
if many factors were present at once or if several conditions occurred
in sequential order. Because of this, repeated findings of low CD4
counts over time could also be a common finding.
Studies looking at the mechanisms that cause low CD4 counts could
also be helpful. The hypotheses presented in some of the articles
reviewed in this paper regarding mechanisms include increased cortisol,
antibody-mediated immune dominance, and malnutrition. It is possible
that several of these could operate simultaneously as well, or that
they could occur sequentially in a cascade. All of the factors presented
here, from infections to psychological stress, could combine in
causing immunosuppression, and many of them could be much more easily
treated than current methods of treating HIV which rely on long-term
use of medications with a number of serious adverse effects.
Finally, the results described here cast doubt on the original claims
that HIV specifically targets CD4+ T lymphocytes. It could be instead
that many or all of the conditions reviewed here operate under the
same mechanism. The search for a new infectious agent began around
1979, when clinicians found extremely low CD4 counts in a few young
male homosexuals who were dying of multiple infections. The ensuing
international scientific search resulted in Robert Gallo's claim
that HIV was the cause, in particular because it infected CD4+ lymphocytes
(Gallo et al. 1984). Based on the results reviewed here, it is very
possible that the low CD4 counts in those early cases were simply
a result of the opportunistic infections that were present, not
because of any new agent that targeted CD4+ T-cells. This argument
is strengthened by the continued difficulty in determining a mechanism
for how HIV destroys CD4+ T-cells. The mechanisms originally proposed
by Gallo have had to be abandoned, and new hypotheses have also
experienced several major revisions over the years. A conference
in 1997 determined that the cause was still unknown (Balter 1997),
and recent articles seriously discredit the reigning hypothesis
that the immune system destroys its own CD4+ T lymphocytes (Roederer
1998). A quote from the article by Balter (1997) which describes
the conference on the causes of low CD4 counts, follows:
“It might be said that AIDS researchers know the virus that
causes the disease, HIV, inside and out. They have isolated its
proteins, sequenced its genome, and identified the receptors it
uses to dock onto the CD4 T lymphocytes that are the viruses primary
target. Yet the central mystery of AIDS remains unresolved: How
does the virus cause the severe loss of CD4 T-cells, which wrecks
the immune system, that is the hallmark of the disease (Balter 1997,
One argument that is commonly used to support the claim that HIV
specifically targets CD4+ cells is that when anti-HIV medications
are given, the CD4 count rises. As described above in the section
on immunosuppressive effects of anti-HIV medications, however, protease
inibitors and AZT specifically inhibit a variety of microbes that
commonly create infections in people diagnosed HIV-positive (PDR
1999, Cassone 1999, Atzori 2000). This finding may explain some
of the rise in CD4 counts that people on these drugs experience,
but there are also other important factors to consider such as the
tremendous psychological relief that these drugs provide for those
who take them. The introduction of protease inhibitors was accompanied
by widespread media acclaim, and this may help them generate a powerful
psychological effect that relieves much of the stress that is associated
with the diagnosis HIV-positive. Because psychological stress lowers
the CD4 count, its relief could allow the CD4 count to rise. Once
a rise in the CD4 count is seen, for whatever reason, the relief
of psychological stress would be strengthened, as would the belief
in the power of the anti-HIV drugs.
About 5-15% of people who are diagnosed HIV-positive do not go on
to show any immunological abnormalities at all, even after ten or
more years (Learmont et al. 1992, Ashton et al. 1998, Walton 1999).
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a period which has been called the latent phase of the virus. Perhaps,
by focusing on AIDS as a multifactorial illness, this latent phase
can be extended indefinitely in more and more people. Further research
that focuses on some of the many factors reviewed in this paper
may reveal why these long-term nonprogressors appear to stay healthy
in spite of being diagnosed HIV-positive, and may help increase
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