CD4/CD8 Cell Counts

“Mindfulness meditation training has stress reduction benefits in various patient populations, but its effects on biological markers of HIV-1 progression are unknown…A diverse community sample of 48 HIV-1 infected adults was randomized and entered treatment in either an 8-week MBSR [Mindfulness-Bases Stress Reduction] or a 1-day control stress reduction education seminar…Participants in the 1-day control seminar showed declines in CD4+ T lymphocyte counts whereas counts among participants in the 8-week MBSR program were unchanged from baseline to post-intervention…This effect was independent of antiretroviral (ARV) medication use.”

“Of 1551 HIV-1-infected individuals screened for helminth [parasitic worm] infection, 299 were helminth infected. 234 adults were enrolled and underwent randomization and 208 individuals were included in intent-to-treat analyses. Mean CD4 cell count was 557 cells/microl and mean plasma viral load was 4.75 log10 copies/ml at enrollment. Albendazole therapy resulted in significantly higher CD4 cell counts among individuals with Ascaris lumbricoides infection after 12 weeks of follow-up and a trend for 0.54 log10 lower HIV-1 RNA levels. These effects were not seen with treatment of other species of soil-transmitted helminths. [implying that at least one species of helminth reduces CD4 counts, and that part of what is known as ‘viral load’ may be due to these parasites]”

“Data from 1686 women were analyzed: 1203 (71.4%) were categorized as non-users, 429 (25.4%) as intermittent users, and 54 (3.2%) as persistent users of crack [cocaine]…Throughout most of the study period, those reporting persistent crack use had higher viral load and poorer immune function, whereas those reporting no use had the lowest HIV-1 RNA levels and best immune health, with intermittent crack users falling in between…We found that the median reduction in HIV-1 RNA level was highest in non-users, at 1.7 log10 copies/µl, compared with 1.4 log10 copies/µl in inactive crack users and 1.0 log10 copies/µl in active users. The median CD4 cell count increase was highest in non-users, at 161 cells/µl, compared with 123 cells/µl in inactive users, and 100 cells/µl in active users.”

“Comparison of mean lymphocyte counts among human immunodeficiency virus-negative Senegalese men and women…CD4…[mean/standard deviation for men] 711.6/332.8…[for women] 851.9/325.0…[for prostitutes] 966.0/366.4 [this means that 13.6% of men (1 SD) can be expected to have CD4 counts between 380 and 46 (encompassing the range for ‘at risk for AIDS’ (<500) to outright AIDS without symptoms (<200)). Women are slightly better off with 13.6% expected to have counts between 527 and 202 and only about 2% below 200. Prostitutes are the best off with 13.6% expected to have counts between 600 and 233]…[Factors associated with lower CD4 counts than average are 1) age below 20 or over 30]; 2) young age at first intercourse (²15); 3) old age at first intercourse (³19); 4) Fever; 5) high blood pressure; 6) cough; 7) diarrhea; 8) weight loss; 9) pneumonia; 10) swollen lymph nodes; 11) oral leucoplacia; 12) more than 8 children; 13) use of oral contraceptives; 14) abnormal discharge; 15) cervicitis; 16) pregnancy; 17) TB; 18) tallness; 19) maleness…[Factors associated with higher CD4 counts than average are 1) Alcohol use (add 67); 2) Current tobaco use (add 115.6); 3 low weight (<51kg); 4) high weight (>60kg);5) Shortness; 6) more schooling; 7) marriage; 8) commercial sex work; 9) birth in Senegal]”

“In tropical countries, notably sub-Saharan Africa, helminth [intestinal worm] infections are the most prevalent parasitic infection. These great immunomodulators have the ability to tip the balance towards T-helper cell type 2 immunity, to decrease vaccine responses, and influence the outcome of major tropical killers. [i.e. intestinal worms can affect CD4 counts, not just HIV]”

“17 609 [HIV-positive people] contributed a total of 30 313 person-years to the analysis of rates of AIDS or death in ART[anti-retroviral-therapy]-naive patients…The first AIDS events occurring at CD4 cell count >350 cells/mL were…examined: 63 (20%) were Kaposi’s sarcoma (compared with 16% overall), 62 (20%) oesophageal candidiasis (17% overall), 42 (14%) tuberculosis (13% overall), 35 (11%) herpes simplex (6% overall), 37 (12%) recurrent bacterial infections (6% overall), 20 (6%) Pneumocystis jiroveci pneumonia (19% overall), 17 (5%) cryptosporidiosis (3% overall) and 13 (4%) lymphoma (3% overall)…[Table 1 shows that the risk of death in 100 person years is 0.32 for CD4 counts 350-499, 0.20 for 500-649 and 0.17 for over 650]…[despite this, the authors conclude]…Our findings suggest that risk of AIDS and death might be reduced by using ART to raise CD4 cell counts even among patients with high CD4 cell counts”

“A runaway cycle in which elevated CD4+ T cell activation and proliferation drive HIV production and vice versa cannot explain the pace of depletion during chronic HIV infection.”

“There are people with HIV who never develop low CD4 T cells, and there are people [with] low CD4 T cell [count]s who do not have HIV.”

“[Lawyer] Turner says 'Physicians treating HIV positive and AIDS patients monitor the number of CD4 cells in the peripheral blood. A decline in their numbers is interpreted as proof the cells are being killed as a consequence of infection...the fact that CD4 cells are [diminished in] the bloodstream does not prove the cells are being killed'; do you accept that?

[Gallo] I would accept that, yes…[long diversion]…the statement as [the lawyer] read it I have no objection to”

“Several mechanisms may contribute to CD4 memory T-cell depletion during primary infection. The major mechanism is a direct cytopathic [cell killing] effect of the virus on infected CD4 T cell…Mattapallil et al showed that 60% of mucosal CD4 memory T cells were indeed infected within 10 days after viral challenge. The majority (80%) of these infected cells disappeared 4 days later, which parallels the plasma viral load decrease. These observations suggest that the high rate of infection of these cells is sufficient to account for their loss during acute infection. No bystander mechanism needs to be invoked [the only problem is that this is not HIV, but SIV, a virus supposedly found in monkeys that produces mild symptoms. This illustrates the lack of any evidence that HIV kills CD4 cells directly]”

“In Canchungo, Guinea Bissau, Wonji, Ethiopia, and East Uganda, 3%–5% of HIV-negative adults had CD4+ cell counts <350 cells/µL…at a given CD4+ cell count, survival was shorter in South Africa than in Zambia. At a CD4+ cell count of 200 cells/µL, for example, the median life expectancy predicted by the model was 2.3 years in South Africa but was 4.0 years in Zambia, and the survival distribution of South Africans with a CD4+ cell count of 500 cells/µL was close to the survival distribution of Zambians with a CD4+ cell count of 350 cells/µL…There are large variations in CD4+ cell count within and among HIV-negative populations. CD4+ cell counts decrease with age and are, on average, ~100 cells/µL higher in women than in men. Infections other than HIV (bacterial, protozoan, and helminthic) may affect CD4+ cell counts. In individuals, CD4+ cell counts may vary by up to 200 cells/µL in readings performed a few weeks apart. Intra- and interlaboratory variation may also contribute to this variation.”

“Soon after infection with HIV, CD4+ cell counts decrease by approximately one-quarter and then decrease slowly thereafter. When the CD4+ cell count reaches ~350 cells/microliter, HIV-related opportunistic infections become evidence; at 200 cells/microliter, the person is classified as having AIDS regardless of the appearance of other opportunistic infections; and at ~50 cells/microliter, patients die. [this is a good statement of the CD4 dogma, although unfortunately not backed up by data]”

“The second and potentially more exciting implication of the findings of Rodríguez et al is that future improvements in the treatment of HIV infection and AIDS may result from improved understanding of the 90% of CD4 cell depletion that remains enigmatic [It is exciting to admit that 25 years into an epidemic supposedly caused by a virus that depletes CD4 immune cells nobody knows how the virus causes it?]”

“The median CD4 cell count when starting HAART has declined in recent years [This is probably mainly due to changes in treatment criteria that increasingly recommend starting AIDS drugs only when CD4 cell counts drop below 200]”

“A retrospective cohort study of patients attending the national HIV referral centre in Singapore who had a CD4 count less than 250 cells/µL and a measurement of body weight performed at the time of starting ART was carried out…A total of 394 patients were included in the analysis, of whom 79 died during a median study follow-up of 2.4 years. Moderate to severe malnutrition was present in 16% of patients at the time of starting ART, and was found to be a significant independent predictor of death…Malnutrition did not impair the magnitude of the increase in CD4 count at 6 or 12 months”

“When compared with pink [finger]nails, ‘grey or DB [distally banded] nails’ was strongly associated with a CD4 cell count of less than 200 cells/microliter.”

“The increase in HIV- and herpes-virus-specific CD4+ T-cell proliferative capacity after 55 months of HAART suggests that the improved proliferative response is not specific for HIV, but reflects a more general improvement of antiviral immune responses, which is induced by HAART…[In this study] Total CD4+ T-cell numbers tended to increase from a median of 400 cells/µl just before HAART to 460 cells/µl at 7.5 months after HAART and 550 cells at 55.5 months after HAART [but note that the median is a measurement that can change drastically without real changes in the data. The median of 1,1,1,100,100 is 1 but the median of 1,1,100,100,100 is 100. The mean (average) is probably a better measure]…[For this study] we selected for patients who were successfully treated with HAART, as was reflected by a decrease in viral load, and an increase in CD4+ T-cell numbers.”

“[according to slide 8, 35% of people were diagnosed with AIDS without any AIDS-defining illness, based solely on a positive HIV test and low CD4 count, in 1993 (the first year this definition came into use) but by 2003 they represented 71% of cases]”

“As far as biology is concerned, says Stillwaggon [a US academic], the immune systems of people in southern Africa are weakened by malnutrition and parasitic illnesses.

First, malnutrition - a deficiency of energy, protein and minerals such as iron, zinc and vitamins - makes a person far more susceptible to infectious and parasitic diseases.

These deficiencies make it hard for new cells to be built, including CD4 cells that protect the body from infections.”

“I was diagnosed HIV-positive a year ago and since then, or perhaps longer, my CD4 count has been below 10. I say perhaps longer because I don't know how long I have had this condition as the possibilities for me to get infected are just about nonexistent. I enjoy extremely good health, I have now and then had problems with yeast infection (due to antibiotic use and contraceptives I think). Since being diagnosed HIV-positive I underwent a series of diet and also lifestyle changes and for a whole year now I have had no problems whatsoever with candida.

At the same time I was diagnosed HIV-positive I underwent a gynecological exam and was diagnosed with a HPV infection in my uterus, going against all advice from specialists I never took ARVs , antibiotics or did laser in order to get rid of HPV. I did a lot through diet, natural therapies, homeopathy and loads more, six months later I repeated the test and the HPV was gone. Funny, hey? How would it go away if my CD4 counts are so low? Was it ever there?

And there is lots more…I would probably have died not knowing my status, was it not for a check up I needed to undergo in order to get under my husband's insurance.”

“many [US] states have passed legislation requiring laboratories to report the names of patients with low CD4+ cell counts [and other tests 'indicative of HIV'] to their state departments of health [California, Colorado, Florida, New York, Pennsylvania and Washington]”

“This population-based cohort of unselected adults in Misisi, a shanty compound in Lusaka, has been under follow-up since 1999, and CD4 cell counts have been followed in participants since the initial survey. No antiretroviral drugs were used by any of the participants over the period of the study…In the survivors, the mean decline over 4 years was 29 cells/micro-liter per year…Our data indicate that the decline in CD4 cell counts over the period from 1999 to 2003 in adults not treated with highly active antiretroviral therapy was slow, and our estimate of the rate of loss of CD4 cells is in very close agreement with the estimate of 21.5 cells/micro-liter per year from Tanzania. These data support the idea that HIV progression to AIDS and death is slower than at first thought, even in very under-resourced populations living in crowded conditions.”

“All types of white blood cells (WBCs) measured in the Complete Blood Count and platelets were significantly decreased in workers exposed to <1 ppm benzene compared to controls. Lymphocyte subset analysis showed significantly decreased CD4+ T cells, CD4+/CD8+ ratio, and B cells. Hemoglobin concentrations were decreased only among workers exposed to ³10 ppm.”

“Reference range for T-lymphocyte subsets…Mean…CD4 Count…720.31…SD [standard deviation]…272.55 [assuming a normal distribution (and its meaningless to report mean and SD otherwise) about 13.6% of healthy Indian adults can be expected to have counts between 448 (just below the point at which ARV treatment is often started in HIV-positive asymptomatic people) and 175 (lower than the count considered automatically AIDS in HIV-positive people in America) and about 2.1% will have a count below 175 (considered ‘AIDS’ even in the absence of disease in America).]”

“CD4(+)-lymphocyte counts (LCs) play a crucial role in the management and monitoring of HIV infection. Variability in CD4(+) LCs has been reported to occur as a result of measurement techniques and/or biological variations. We report on the CD4(+) LCs of healthy human immunodeficiency virus (HIV)-seronegative adults in Botswana. Samples were obtained from HIV-seronegative blood donors. The median CD4(+) LC was 726 cells/mm(3) (for females, 782 cells/mm(3); for males, 698 cells/mm(3)). The median CD8(+) LC was 488 cells/mm(3) (for females, 494 cells/mm(3); for males, 485 cells/mm(3)). The median CD4(+)-to-CD8(+) ratio was 1.57 (for females, 1.66; for males, 1.51). Our findings of low CD4(+) LCs among HIV-negative adults in Botswana are significant and have important implications for the management of HIV disease in the population of this sub-Saharan African country. [This means that about 13% will have counts under 500 (the point at which HIV+ people are often put on AIDS drugs] and about 2% will have counts diagnostic of ‘AIDS’ in the US]”

“a total of 614 healthy native Chinese adults who met inclusion criteria were studied. Of these, mean age was 33.4 years (range, 16 to 50 years), and 377 (61.4%) were male…CD8 lymphocyte counts, which averaged 539.6cells/microliter, were significantly higher in men than in women, resulting in a significantly lower CD4/CD8 ratio in men. We observed a mean CD4 level of 727 cells/ l for the healthy, HIV antibody-negative Chinese adult residents of Shanghai, with no significant differences according to age or gender. [Table 1 shows that the range of CD4 cell counts was 252-2082, CD8 counts were from 193 to 1071 and the CD4/CD8 ratio varied from 0.47 to 4.62. Note that a CD4 cell count less thann 200 or a CD4/CD8 ratio less than 0.14, along with a positive HIV test and no illness, constitutes 'AIDS' in the US]”

“Among the [55] antiretroviral non-naive patients, 21 had never [had a] CD4 T-cell [count] below 500/cubic-millimeter before HAART was started [indicating that despite the belief that AIDS is a disease of immune-suppression many of these patients were defined as AIDS in the absence of evidence of immune suppression]”

“As in other studies, we found that survival was not influenced by demographic characteristics or CD4 lymphocyte count”

“[Dr. Brian] Gazzard [retiring chair of the British HIV association] had his own Aids scare. “I pricked myself on a needle. One of the other doctors said: ‘Well, now you’ll know what its like to be HIV positive’. I spent three agonising months waiting till I could take the test, and two sleepless nights waiting for the results. I did it anonymously at another hospital. “It was negative, but in the process they discovered I happened to have an unusually low CD4 count - 350 - which has stayed that way ever since.” [Dr. Gazzard is healthy.]”

“Baseline CD4 count was the strongest predictor of subsequent clinical progression”

“After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in [the other three] groups [of HIV-positive people taking antiretroviral therapy], when measured after 6, 12, and 18 months of treatment.”

“A total of 1078 human immunodeficiency virus (HIV) type 1-infected women from Tanzania were randomized in a placebo-controlled trial using a factorial design to examine the effects of supplementation with vitamin A (preformed vitamin A and beta carotene) and/or multivitamins (vitamins B, C, and E). Supplements were given during pregnancy and lactation [breastfeeding]. Children of women in the multivitamin arms had a significantly lower risk of diarrhea than did those in the no-multivitamin arm. The mean CD4+ cell count was 151 cells/microL higher among children in the multivitamin arms than among those in the no-multivitamin arm [although not with Vitamin A, indicating that CD4 cell counts can be increased in ways other than giving anti-HIV drugs]”

“Among patients with <50 million cells/l the adjusted relative hazard of mortality was 5.07 for patients of experienced physicians and was 11.99 among patients with inexperienced physicians, in comparison to patients with >200 million cells/l treated by experienced physicians. Similarly, among patients with >50 million cells/l, the adjusted relative hazard of mortality was 6.19 for adherent patients and was 35.71 for non-adherent patients, in comparison to adherent patients with > 200 million cells/l”

“Overall, neither the number nor the differentiation phenotype, including perforin levels, of HIV-1-specific CD8+ T cells appear to be correlated directly with the non-progressor state [CD8 cell counts are often taken in conjunction with CD4 cell counts as representative of the state of the immune system]”

“Collectively, these observations indicated that qualitative factors within the CD8+ T cell response, not measured by current assays, may be the principal determinants of control over HIV replication and disease progression…The differential capacity of CD8+ T cells of LTNPs [Long-Term Non-Progressors] to proliferate when stimulated with HIV-infected CD4+ T cells is a measure of antiviral effector function that has permitted us to distinguish the HIV-specific CD8+ T cell response of these patients from those with progressive HIV infection. Differences in suppressive activity, beta-chemokine secretion, direct cytotoxicity, frequency, peptide specificities or expression of IFN-gamma, tumor necrosis factor alpha or IL-2 by HIV-specific CD8+ T cells did not account for differences in restriction of HIV replication…So far we have been unable to detect diminished production of IL-2 or other cytokines in the HIV-specific cells of progressors that would be typical of functional defects described in animal models consistent with anergy, clonal exhaustion or deficient T cell help. [In other words, there are no tests that can distinguish the immune system of those who will progress to AIDS, and those who will not. And, as usual, other disease factors than HIV are not considered]”

“According to one paradigm [the one that made Dr. David Ho briefly famous], the demand for CD4 T cell production in response to rapid virus-mediated destruction is the direct cause of increased turnover. Progressive depletion of CD4 T cells is accordingly seen as a failure of production to keep up with the rate of loss. This hypothesis has been challenged on several grounds…The quantitatively similar association between CD4 depletion and immune activation in HIV-1 and HIV-2 infections we report in this work supports the hypothesis that immune activation drives depletion…It is very unlikely that the similar rates of CD4 T cell turnover, found in HIV-1 and HIV-2 patients with comparable levels of CD4 depletion, are associated with similar turnover rates of infected cells despite the large difference in viremia levels.”

“Hydroquinone [the active ingredient in most skin lightening creams] may, at least in part, increase allergic responses via the enhancement of IL-4 production by CD4+ T cells…IL-4, mainly produced in CD4+ Th2 cells, is an important stimulus for the switching of antibody isotype to IgE in both mice and humans.”

“A total of 84 apparently healthy HIV negative [Indian] volunteers in the age group of 20-59 yr were included…All 84 volunteers were found to be HIV negative [by ELISA]…The lower limit in men and women for absolute CD4 count were 265 and 415 cells/microliter respectively…A low [CD4:CD8] ratio, particularly when associated with an absolute decrease in the number of CD4 cells, has been highly correlated with the clinical diagnosis of AIDS. Lifson et al suggested that a ratio below 0.85 should raise the suspicion of AIDS…The lower limit of CD4:CD8 ratio observed [in this study] was 0.64.”

“Researchers need to establish what constitutes 'normal' blood levels of CD4 cells in different populations in developing countries.”

“Some serious illnesses, especially active tuberculosis and bacteremic pneumonia, may occur when the CD4 cell count is above 200/microliter…The available data from cohort studies, with one exception, have not been able to define a CD4 stratum above 200 cells/microliter at which patients benefit from initiation of therapy…In persons with CD4 cell counts above 350/microliter, risk of 3-year clinical progression [to AIDS] is low and additional concerns about impact of antiretroviral regimens on quality of life, risk of serious adverse drug effects, and limitations on future treatment options generally outweigh the benefits of durable viral suppression.”

“The controversy currently revolves around one key question: at what CD4+ cell count can the greatest benefit of therapy be achieved with the lowest possible risk of disease progression, drug toxicity, and drug resistance?…[a little later]…if the goal of therapy is to halt further immune deterioration, starting treatment when the CD4+ cell count is between 200 and 350 cells/mm3 may be sufficient. However, if the goal is more complete CD4+ cell restoration, early initiation of therapy may be more effective. [where was all that talk about drug toxicity and disease progression? That seems to have vanished from consideration.]”

“The median percentage of CD8+ T lymphocytes increased from 38% at entry to 44% at follow-up in the 21 HIV-infected children with measles studied at both time points (P = .02). In contrast to the median number of CD4+ T lymphocytes, the median number of CD8+ T lymphocytes increased 2-fold from 1169 cells/mm3 at entry to 2477 cells/mm3 at follow-up in these 21 coinfected children (P = .002). The median percentage and number of CD8+ T lymphocytes in coinfected children were approximately double those in HIV-uninfected children with measles and HIV-uninfected control children.”

“Consistent with the analyses reported here, these data indicate that direct virus-induced killing of infected CD4+ T cells alone cannot account for the numerical and functional depletion of CD4+ T cells leading to AIDS. Rather, AIDS progression reflects a complex balance between the direct impact of the virus and the nature of the host response to the infection [using SIV, Simian Immunodeficiency Virus as a model for HIV]”

“HIV-infected gay or bisexual men between 18 and 55 years old with one or more non-AIDS-defining symptoms or a T-helper-inducer cell (CD3+CD4+) count of 200–700 cells/mm3 who were fluent in English were recruited…We excluded men with major psychiatric diagnoses, signs of gross neurocognitive dysfunction, or full-blown AIDS…[On group of] the participants [were] randomly assigned to cognitive behavior stress management…The participants in the control condition completed a 10-week waiting period and underwent assessments identical to those received by the participants assigned to cognitive behavior stress management (and at equivalent time points)…An analysis of covariance…revealed a significantly greater number of naive T cells at follow-up among the subjects who participated in cognitive behavior stress management than in those assigned to the control condition. While the participants receiving stress management showed a small increase [in T cells] over this period, the control subjects showed more than a 25% decline. At study entry there was no difference in HIV viral load between the stress management group…These groups did not differ in HIV viral load or antiviral medications either before or after the intervention [suggesting that HIV medication was associated with a significant decline in CD4 counts]”

“The median CD4 cell count increased over time for each treatment group (91 at TB diagnosis and 300 at 12 months for no ARV [anti-retroviral therapy]; 65 and 160 for dual ARV and 59 and 144 for HAART [Highly Active Antiretroviral Therapy, including 3 or more drugs] ... [Note that CD4 cell counts were about double in TB patients not taking AIDS drugs!]”

“We did not find that the level of immunosuppression [CD4 counts in HIV+ African gold miners] increased the risk of overall recurrence, relapse, or reinfection [with Tuberculosis, an AIDS-defining condition in HIV+ people]”

“Two years before the virus that causes AIDS was discovered, physicians in the United States and Europe realized that the defining symptom of the mysterious new disease was the loss of a specific immune system cell population, called CD4 cells. Twenty years later scientists still don't know what kills the cells [but, gee, we all thought it was HIV!]. And its eventual discovery will be key to understanding AIDS - defined as a rise in the numbers of viruses in the bloodstream coupled with a fall in the CD4 cell count. [However]...it is not in HIV's interests to kill off its "home" [CD4] cell, most scientists believe a complex interaction is at play, causing the cells' deaths [translation: HIV doesn’t kill CD4 cells and therefore cannot be the cause of AIDS]”

“women with chronic depressive symptoms were 2 times more likely to die than women with limited or no depressive symptoms. Among women with CD4 cell counts of less than 200/µL…Chronic depressive symptoms were also associated with significantly greater decline in CD4 cell counts after controlling for other variables in the model, especially among women with baseline CD4 cell counts of less than 500/µL and baseline viral load greater than 10000 copies/µL.”

“Declining host selenium levels...inhibit CD4 T cell production, which permits opportunistic infectious pathogens to proliferate. These pathogens in turn lead to further depression of serum selenium levels and associated decline in CD4 T cell count”

“HIV-1 infects CD4+ T cells but direct infection and killing of these cells can only partly account for HIV-1-associated lymphocyte depletion. The actual number of productively infected cells is estimated to be relatively low, in the order of 5 X 10^7 to 5 X 10^8 CD4+ T cells whereas the human body contains an average of 2.5 X 10^11 CD4+ T cells. Direct infection of CD4+ T cells does not explain the loss of naive CD8+ T cells that parallels the decline in naive CD4+ T cells during asymptomatic HIV-1 infection.

More important in this respect may be the response of the immune system. HIV-1 activates the immune system persistently because of high and continuous virion production and possibly by viral gene products such as Nef.”

“A total of 151 Eth. [Ethiopian] and 31 Isr [Israeli]. individuals were studied; 111 of the Eth. subjects had been in Israel for fewer than 12 months and did not receive anti-helminthic [intestinal worm] treatment at the time of their examination. More than 80% of them were heavily infested by one or more helminthic parasite, as determined by stool examination. Forty-eight Eth. subjects had been living in Israel 3–10 years, and although they received anti-helminthic treatment, in the stool of about 15% of them, we found a few eggs of Schistosoma mansoni or Trichuris trichuria. All Isr. subjects were free of helminthic parasites, and all individuals were HIV-seronegative as determined by ELISA…We have previously suggested that the decreased CD4 levels and significantly lower CD4/CD8 ratio in the new-Eth. group, compared with the Isr. group, is a consequence of immune activation…Worsening the situation is the finding that the new- Eth. individuals studied had significantly less CD4+ cells, less naive (CD45RA+) cells, more memory (CD45RO+) cells, and increased CTLA-4 expression on CD4+ cells than did the Isr. cohort…Clearly, the diminished number of CD4+ cells and the lower percentage of naive cells in these individuals lessen their capacity to mount effective immune responses”

“[The CDC National STD and AIDS Hotline Responds] If a person has been diagnosed with an AIDS Indicator Disease, then that person meets the 1993 AIDS Surveillance Case Definition, regardless of their CD4 count.”

“Previously published data on CD4 cell count changes during therapy interruptions have mainly consisted of reports on very small numbers, but there has been a tendency to observe a distinct fall in numbers. The relatively rapid early fall in CD4 cell count after interrupting therapy may correspond to the relatively rapid increase in CD4 cell count after initiating therapy, which has been ascribed to the redistribution of cells from the lymphoid tissue [i.e. CD4 cells may not be increased with antiretroviral therapy, merely shuffled around the body to places where they are easier to measure]”

“Several of the features of Leishmania infection are reminiscent of HIV infection. In both, there is a decrease of CD4 lymphocytes, the immune activation profile is similar, and a dominant TH2 profile is present...All helminthic infections are associated with strong chronic immune responses...[including] decreased CD4 and CD4:CD8 ratios”

“Controversy continues regarding the effects of HAART on CD4 T-cell production...our understanding the mechanisms that lead to depletion of CD4 T cells remains incomplete. The observation that T-cell turnover in SIV-infected mangabeys appears to be normal, despite high viral loads, has reinforced the hypothesis that indirect mechanisms may be largely responsible for increases in T-cell turnover, yet there is little solid evidence on how HIV and SIV mediate this effect [translation: we don’t have a clue how HIV kills CD4 cells]”

“The data should also serve as a strong reminder that using the CD4+ cell count as a surrogate for HIV testing has a risk of markedly overestimating the diagnosis of HIV. Therefore, CD4+ cell counts should not be relied on for a presumptive diagnosis of HIV in lieu of consent for serologic testing. Finally, a larger study of CD4+ cell counts in critically ill individuals might better define the prognostic value of a low result.”

“the perturbations of T cell immunity induced by HIV are considerably more complex than a direct cytopathic effect on memory CD41 T cells”

“Tenfold (1 log10) incremental increases in maternal HIV RNA were associated with a 1.9-fold increase (95% confidence interval [CI], 1.2-2.9) in transmission and a 2.1-fold increase (95% CI, 1.3-3.5) in infant mortality (P<.01). Maternal CD4 cell counts and demographic and medical characteristics were not significant predictors of transmission. However, maternal CD4 cell counts below the median (400/mm3) were significantly associated with infant mortality (P=.035, Fisher's exact test) [i.e. CD4 cell counts might predict ill-health, but don’t seem to be particularly associated with HIV/AIDS]”

“breast-fed [healthy, HIV-negative] infants had fewer CD4 T cells and a great number of NK [natural killer] cells than the age-matched formula-fed infants...suggesting greater maturity in the development of the immune system of breast-fed infants”

“This analysis confirms that the rate of removal of CD4+ T cells is indeed elevated and the half-life is indeed shortened in the HAART group [i.e. therapy might raise the level of CD4+ cell counts, but they are not the same as normal immune cells, and might not be doing any good]”

“A reliable relationship exists between ALC [total lymphocyte/white blood cell count] and CD4 count. In a similar population, an ALC less than 1,000 cells/mm3 is predictive of a CD4 count less than 200 cells/mm3 and an ALC greater than or equal to 2,000 cells/mm3 is predictive of a CD4 count greater than or equal to 200 cells/mm3”

“Margolick...and, independently, Adleman and Wofsy proposed the BH [Blind Homeostasis] hypothesis. They postulated that, normally, a constant number of T lymphocytes is maintained regardless of the CD4 to CD8 ratio...[and] would necessarily lead to a progressive depletion of the CD4 compartment in HIV infection if CD4 cells are preferentially destroyed by the virus...[based on the detailed analysis in this paper] we consider the original BH hypothesis and also its more elaborate version to be biologically rather implausible...If correct, the BH hypotheses, but not the alternative hypothesis, could account for CD4 cell depletion by HIV. However, as we have discussed, there is no compelling evidence in favor of BH, either inherent or HIV imposed...these considerations also suggest a need to reevaluate current concepts about HIV pathogenesis, including the concept that a systemic depletion of CD4 T cells is the hallmark of the disease.”

“In this issue of Nature Medicine, reports by Pakker et al and Gorochov et al provide the final nails in the coffin for models of T cell dynamics in which a major reason for changes in T cell numbers [such as CD4 cells] is the death of HIV-infected cells…the facts (1) that HIV uses CD4 as its primary receptor, and (2) that CD4+ T cell numbers decline during AIDS, are only an unfortunate coincidence that have led us astray from understanding the immunopathogenesis of this disease. HIV leads to the progressive destruction of all T cell subsets, irrespective of CD4 expression. Ultimately, AIDS is a disease of perturbed homeostasis. Only when we understand how the body regulates T cell numbers will we be able to find the mechanism(s) by which HIV destroys the immune system.”

“The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells.”

“We present two cases of severe PCP [pneumocystis carinii pneumonia] in infants who were perinatally exposed to HIV [and AZT] but who were uninfected with HIV…Both children had a transient decrease in their CD4 cell counts that was concomitant with the acute PCP episode”

“A total of 169 patients had at least one measured CD4+ T-cell count of less than 5 million/l and were included in the analysis. This represented 12% of the total population of approximately 1450 HIV-positive patients seen in the two centres since 1980…A total of 122 deaths had occurred, out of these 166 patients, by the end of the follow-up period. Although the median survival was 0.95 years, one-fifth of patients (19.4%) remained alive for over 2 years…Although the routine measurement of CD4+ T-cell counts had been carried out at the Royal Free Hospital since 1982, the first recorded count of less than 5 million/l or less was in 1989. Although a number of infected patients registered at the hospital had developed AIDS and died before 1989, none had a CD4+ T-cell count this low prior to death. Thus, this study may have provided some evidence of the effectiveness of antiretroviral and prophylactic regimens currently recommended, at least in keeping patients alive long enough for their count to drop to this low level. [but HIV is supposed to cause low CD4 cell counts and AIDS drugs are supposed to raise CD4 cell counts! This is, at best, convoluted logic]”

“A recent report suggested the possibility of a distinct group of long-term nonprogressors who may experience patterns of [CD4 cell count] decline different from those of other individuals. Others have suggested rapid CD4 cell decline at late stages of disease. Multilevel modeling methods, while allowing individual patterns of decline to vary, assume there is an underlying common pattern of decline shared by all persons. Thus, such methods may not be the most appropriate for establishing the existence of subgroups with very different patterns of cell decline…we cannot rule out the possibility that some persons maintain high CD4 cell levels for long periods and that others may experience rapid cell decline at very late stages of disease.”

“The summary of results from a 1993 state-of-the-art conference shows that the effect of treatment on the most popular surrogate, the CD4 cell count, did not accurately predict the effect of treatment on the clinical outcomes, that is, progression to AIDS or time to death”

“The CDC definition of idiopathic CD4 lymphocytopenia [HIV-free AIDS] does not include any clinical parameters. [One group] comprises a series of individuals...who have CD4 counts which are low but in whom there is no clinical evidence suggestive of immunodeficiency...[Some of these are] individuals whose CD4 counts are below the lower end of the normal range and who have constitutionally low CD4 blood levels consistently over a period of time without ill effect…their low CD4 counts may have no prognostic significance”

“Despite its value as a general marker of disease stage, the CD4 count alone is inadequate as a means of measuring prognosis [i.e. declining counts do not necessarily predict AIDS, and vice-versa]”

“[Out of 565 blood donors from Sydney] three donors were found to have absolute CD3+CD4+ counts below the critical level of 300 cells per µL [500 is considered the lower limit of ‘normal’ and counts below 200 are automatically ‘AIDS’ when accompanied with a positive HIV test in the United States]…[One of these three blood donors was determined to have a thyroid problem, one was unavailable for further testing, but the third tested negative for HIV and HTLV-I…] He was referred for immunologic investigation to his own doctor, who found that he was clinical well…The CD4:CD8 ratio was below the normal range in every sample from Donor 3 that was tested…Smokers had a higher WBC [white blood cell] count…the absolute CD3+CD4+ count was increased by approximately 20 percent for smokers versus nonsmokers (both men and women) [and was statistically significant]…Testing of all 12 staff volunteer donors before and after donation showed that donation causes a drop in the absolute count of all the [white blood cell] subsets measured…The CD3+, CD3+CD8+, CD19+, and CD3-CD56+ counts were markedly reduced in number; the CD3+CD4+ count was less so.”

“In clinical practice, a CD4+ T cell count of <500 cells/microliter is commonly used as a trigger to initiate antiretroviral therapy. This practice requires reevaluation in light of our observations that subjects with CD4+ T cell counts of >=500 cells/microliter can progress as rapidly to AIDS and death as those with much lower counts”

“The primary data come from the Edinburgh City Hospital Cohort up to 1 January 1992…dominated by a group of young injection-drug-users…recruitment to the cohort began in October 1985…The first nine representatives of the data set are shown in Figure 1 with CD4 graphed on the root scale and simple individual linear regressions superimposed; vertical bars mark the initiation of AZT treatment. (Note that, by chance, this group contains the only member of the 164 study patients to demonstrate an apparent immunological improvement in the study period!) [6 of these graphs have data points after the initiation of AZT and in 5 out of 6 cases, the steady downward trend in CD4 counts continues]…The estimated variance of individual slopes [rate of lowering of CD4 cell counts] is 1.9, there being considerable individual variation in rate of CD4 loss”

“In 468 consecutive healthy blood donors…the absolute number of CD4+ T lymphocytes differed significantly between males and females (mean 903± 308 cells per cubic millimeter versus 1,018±319, respectively); [a graph in Figure 2 shows that 17 or 18 people (3-4%) had CD4 counts below 500, considered the 'danger zone' with under 200 being outright AIDS]…our data indicate that the 'normal range of the CD4/CD8 value routinely used at present in the immunological laboratory is not valid for the general population. Little attention has been given to the influence of factors such as age and sex on the balance between circulating CD4+ and CD8+ T lymphocytes in humans”

“[a study of the CD4 cell counts of 102 intensive care unit admissions] Our results demonstrate that acute illness alone, in the absence of HIV infection, can be associated with profoundly depressed lymphocyte concentrations [e.g. CD4 cells]. Although we hypothesized that this depression would be directly related to the severity of illness, this relationship 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”

“We found no additional clinical benefit from the immediate use of zidovudine [AZT] in asymptomatic, HIV-infected subjects with 500 or more CD4 cells per cubic millimeter as compared with subjects who began to receive zidovudine only when their CD4 cell counts declined below 500 per cubic millimeter. This was the case despite a significant zidovudine-associated slowing in the decline of CD4 cell counts.”

“The understanding of the pathogenesis of AIDS has probably suffered seriously from two major shortcomings. First, HIV has been wrongly...assumed to be cytopathic in vivo and second, for obvious practical reasons, only peripheral blood has been analyzed and therefore CD4+ T-cell counts in blood have captured too much attention. As stated above, there is good evidence that many host cells other than CD4+ T cells are infected by HIV, and there is no convincing evidence that HIV is cytopathic [kills cells] in vivo [in human beings as opposed to in a test tube (’in vitro’)]”

“Peripheral CD4+ lymphocyte counts were significantly lower [on average] in the patients with primary HIV infection than in the non-converters and seronegative controls [but there was significant overlap in the ranges between all groups: Seroconverters: 110-990; Non-converters: 180-1364; Mononucleosis: 410-1080; HIV-negative: 384-1508; HIV-positive asymptomatic: 224-1080; and HIV-symptomatic: 5-609. Someone with a CD4 count of 500 for example, could be in any group]”

“The distribution of CD4 lymphocyte counts by HIV status and type of tuberculosis is shown in table 1. Greater proportions of HIV-positive tuberculosis patients than HIV-negative patients had CD4 lymphocyte counts of less than 200/µL and less than 500/µL…Response to treatment with clearance of acid-fast bacilli from sputum was high in both HIV-positive (102/110, 93%) and HIV-negative patients (195/213, 92%); rates of cure among HIV-positive patients did not differ significantly by CD4 count.”

“In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years...We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease.”

“There was no consistent pattern in CD4 cell counts with progression of disease [in young European HIV+ children]. Evidence of immunologic impairment as measured by CD4 count was more common than clinical manifestations of HIV infection. An estimated 17% of infected children who had not yet developed AIDS had ever had a CD4 count below the third percentile by 6 months of age, about 34% by age 1 year, and 54% by age 3 years…there was no clear association between CD4 cell count and onset of disease or death, or between CD4 levels before and after AIDS”

“Cocaine is reported to be immunotoxic…Our experimental data confirm that exposure of normal human T cells to micromolar concentrations of cocaine modulates T-cell responses to stimulation by a variety of stimuli, and indicate that cocaine impairs early activation events during CD4+ but not CD4- T-cell stimulation…Our data support the proposition that cocaine abuse may place cocaine-abuser HIV-seropositive individuals at increased risk of opportunistic infections [but the experiments used blood cells from HIV-negative, healthy people, so presumably apply to people regardless of their HIV status]”

“CD4 [immune cell] count fell less rapidly with high-purity [Factor VIII clotting] products.”

“The median CD4 lymphocyte count did not differ in the 3 groups: 54 for the group receiving neither antiretroviral nor P. carinii pneumonia prophylaxis, 53 for the group receiving only antiretroviral therapy, and 52 for the combined treatment group. There were also no major differences in the median CD8 lymphocyte count of the 3 groups [indicates that CD4 cell counts are not always improved by treatment]”

“52 centres in 17 [European] countries participated in the study. Centres provided data on all patients diagnosed with AIDS between 1979 and 31 December 1989…For patients with konwn CD4 cell counts there was a significant association between CD4 cell count and survival”

“We found that among those with CD4 lymphocyte counts less than [200 per cubic millimeter], survival was highly dependent on clinical status [i.e. current health]. Those who were asymptomatic or were symptomatic but with no AIDS-defining clinical conditions had considerably better survival outcomes than those who had clinical AIDS, suggesting that while CD4 lymphocyte count is a reasonable predictor of duration of survival among homogenous clinical groups, the presence of a clinical AIDS-defining condition plays a major role [i.e. CD4 cell counts, by themselves, are not good predictors of survival in HIV-positive people]”

“The results of Concorde [a clinical trial of AZT]…call into question the uncritical use of CD4 cell counts as a surrogate endpoint for assessment of benefit from long-term antiretroviral therapy”

“In this report, we present data on the prevalence of CD4+ T-lymphocytopenia [low CD4 cell counts in HIV-negative people] among healthy, volunteer, anti-HIV-1-negative blood donors…Five (0.25%) of 2030 index donations had a CD4+ count <300 cells per micrometer or a CD4+ percentage <20%”

“In this report we present data on the prevalence of CD4+ T-lymphocytopenia [low CD4 counts] among healthy, volunteer, anti-HIV-1-negative blood donors…5 (0.25%) of 2030 index donations had a CD4+ count <300 cells per µL or CD4+ percentage <20…CD4+ counts for these donors ranged from 81 to 407 cells per µL; CD4+ percentage values ranged from 16 to 32 percent. All five subjects had donated blood frequently without deferrals due to medical history, positive laboratory screening tests, or reported complications in transfusion recipients…Prior to the index (low CD4+ count) donation, none had any of the risk factors associated with acquisition of HIV infection…The lowest CD4+ count (81 cells/µL) was seen in a previously healthy 44-year-old man diagnosed with myositis [muscle inflammation] following his index donation in 1990 and subsequently treated with low-dose prednisone and methotrexate. A second person had received a transfusion during coronary artery bypass surgery 1 month after the index donation. A third patient had an episode of angina the day after donation, and a fourth had a recognized bout of arrhythmia 2 months later. The fifth donor had no clinical findings. At follow-up [August 1992], CD4+ cells ranged from 392 to 565 cells per µL and CD4+ percentage from 22 to 48 percent…All of the retrovirus studies were negative.”

“The magnitude of the within-subject variation in CD4 cell counts was examined by comparing the CD4 cell counts at week 0 (just before the start of trial treatment) with those at week 8. The average decline in this period was very small (~2%), and, as the time between measurements was short, the changes in a patient’s CD4 cell count can be attributed primarily to biological variation or measurement error (or both)…The correlation between these measurements was 0.72, but there were some large changes from one CD4 cell count to the next in some subjects…a CD4 cell count half or double a previous week was not uncommon”

“Some HIV-infected individuals have remained healthy for more than 15 years following seroconversion. Lower numbers of CD4+ peripheral blood lymphocytes have generally been found to indicate the advancement of HIV disease... [but] The CD4+ cell counts vary from day to day and laboratory to laboratory, and similar levels do not necessarily reflect the same disease status in all patients. For example, very low CD4+ cell counts (less than 0.05x10 billion/L) usually indicate advanced disease; however, some patients with these levels remain asymptomatic for extended periods of time while others succumb rapidly”

“More than 15% of the HIV-1-seropositive [IV-drug-using] individuals had plasma vitamin A levels less than 1.05 micromol/L, a level consistent with vitamin A deficiency. The HIV-1-seropositive individuals had lower mean plasma vitamin A levels than HIV-1-seronegative individuals (p<.001). Vitamin A deficiency was associated with lower CD4 levels among both seronegative individuals (p<.05) and seropositive individuals (p<.05). In the HIV-seropositive participants, vitamin A deficiency was associated with increase [indicates that CD4 cell counts can be modified by things other than HIV]”

“We designed a multicentre, prospective, randomised, controlled study of symptom-free HIV-infected patients with haemophilia A who were assigned to receive either an intermediate-purity [Factor VIII blood clotting factor] or monoclonal-antibody-purified [‘high purity’] product…35 completed the 3 year study, 20 in the monoclonal arm and 15 in the intermediate-purity arm [many in this arm leaving to start on high purity Factor VIII]. Among those completing the study, there were no differences between the two groups in the occurrence of AIDS-defining diagnoses (1 in each group). There were, however, striking and significant differences in terms of changes in absolute CD4 counts. The group receiving monoclonal-antibody-purified concentrates had essentially stable counts while a significant drop was observed in the group receiving intermediate-purity F[actor] VIII. These differences were independent of the use of antiretroviral therapy.”

“Biological variability may be even greater in magnitude [of CD4 and CD8 cell counts] than analytic variability. First, circannual (seasonal) rhythms may occur, with a 13% change from week to week in total lymphocyte counts and with substantial alteration in absolute CD4 and CD8 counts from month to month. No such variability was seen in the CD4:CD8 ratio or in the total number of CD3+ T lymphocytes, however, and persons maintained a fixed, discrete range of CD4 values when followed for periods of 2 or 5 years, even among those with initial values less than 300/mm3. Other quantifiable factors that can influence these cell populations include age, sex, ethnic origin, circadian rhythm, physical and psychological stresses, drugs (such as zidovudine [AZT], cephalosporins, cancer chemotherapeutic agents, nicotine, adrenal and gonadal steroids), antilymphocyte autoantibodies, and splenectomy. Sex need not be taken into account when assessing CD8 counts. In one study, however, the mean CD4 percentages were greater for women than for men by 3.5% (P = 0.0001), and the CD4:CD8 ratio was 0.17 units greater for women than for men. Age also does not affect CD8 values, but an increase of 1.1% per decade occurs in the percentage of CD4+ cells, and a 0.09-unit-per-decade increase in CD4:CD8 ratio in persons older than 20 years. Without appropriate correction, as many as 10% of elderly patients (>70 years) would be classified as having values higher than published “normal ranges”…It has been suggested that…persons with an absolute CD4 count physiologically “set” significantly below the means…, if infected with HIV, might be expected to progress to a clinical definition of the acquired immunodeficiency syndrome (AIDS) at a more rapid rate than a patient whose baseline CD4 counts were significantly greater than the mean. Some anecdotal data support this contention, but no evidence exists that these persons are otherwise compromised immunologically.”

“CD4 cell counts and percentages were obtained from 1,246 HIV-seronegative subjects...Nine had at least one CD4 cell count of <300 cells/micrometer or a CD4[:CD8 ratio] <20%...Four subjects had CD4 counts <300 cells/micrometer or CD4 < 20% for two points in time, meeting the current surveillance definition for ICL [HIV-free AIDS]...We also examined the data for the 21 subjects who had one CD4 count between 300 and 500 cells/micrometer and for whom there was at least one follow-up data collection. None of these subjects progressed to a CD4 cell count of <300 cells/micrometer or a CD4<20% at any follow-up visit. Five of these 21 subjects later seroconverted for HIV [indicating that low CD4 cell counts preceded infection, and could not have been caused by HIV]”

“36 subjects treated with high-purity [Factor VIII blood clotting] concentrate for 6 months or more had a smaller decline in CD4 than 72 matched controls on intermediate-purity concentrate. In a more complex analysis with 226 subjects, CD4 counts declined 3% less per 6 months with high-purity material than with intermediate product (p = 0.04).”

“A broad spectrum of diseases, infectious and non-infectious, can cause a fall in CD4+ cell count [they then list several, in the categories of Viral, Rickettsial, Fungal, Protozoal and Bacterial infectious diseases, autoimmune disorders, malnutrition, congenital disorders, drugs, lyphoproliferative disorders and 'other' (for which they include old age and pregnancy)] A transient fall in CD4+ count seems to be frequent in some infectious diseases…Malnutrition, autoimmune diseases, thymoma [benign thymus tumour, and diverse rare congenital disorders have been associated with acquired immunodeficiency, causing CD4+ cell depletion by other mechanisms”]

“A 37-year old man presented with pruritus, night sweats, and cough. He denied risk factors for HIV infection. He had enlarged liver, spleen, and lymph nodes, but declined investigation for 6 months, by which time he also had anorexia, weight loss, productive cough, and breathlessness. His white cell count was 10,200/microliter (lymphocytes 600/microliter)…Biopsy studies revealed reactive lymph-node changes and pneumocystis carinii pneumonia (PCP). CD4, CD8 and Ig levels were low. Tests for HIV-1 and HIV-2 antibody, p24 antigen, and HIV env sequence were negative on two occasions. 9 months later he had an ulcerating lymph-node mass in the groin and hard, purple nodules over his trunk…tests for HIV (and HTLV-I) were again negative…The second patient was a 46-year-old male liver transplant recipient with a history of tuberculosis in childhood, legionella pneumonia, salmonella septiciemia, and recurrent shingles. He denied risk factors for HIV infection. His maintenance immunosuppression was prednisolone, azathioprine, and cyclosporin. 3 months after transplantation PCP developed. CD4 and CD8 counts were low but an HIV antibody test was negative…Over the next 6 months he had repeated bacterial pneumonia and cholangiitis [inflammation of the bile duct], multidermatomal shingles, and disseminated eczema herpeticorum. HIV antigen, antibody, and env sequence tests were negative.”

“In 1984 we established a cohort of 965 intravenous drug users participating in drug treatment programmes in New Jersey and we have been following up this cohort with serological testes for HIV infection and lymphocyte subsets. 623 were HIV seronegative on study entry; and so far, 50 HIV seroconverters have been found. 106 men and 74 women have been HIV seronegative at all times and have had flow cytometry done at least once. For those studied more than once, we calculated mean CD4 counts and the CD4/CD8 ratios…3 men and 2 women in this HIV-seronegative cohort have CD4 counts below 500/microliter. All 5 are alive, and we have serial data confirming CD4 counts below 500/microliter for 3 of these patients, with different patterns exhibited. HIV-1 p24 antigen, HIV western blot, and HTLV serology are negative in all 3 and family histories are negative for diseases or syndromes associated with congenital immunodeficiencies.”

“[The abstract states, without qualification, that] In the two didanosine groups, there were improvements in the number of CD4 cells [the immune cells whose depletion is supposed to be a 'hallmark' of AIDS] and in p24 antigen levels, as compared with the zidovudine [AZT] group…[but the paper later admits that] In the subjects receiving didanosine, CD4 cell counts increased during the initial 8 to 12 weeks of therapy and then began to decline. In the subjects treated with zidovudine, CD4 counts tended to decline throughout the study period…[Table 4 in this paper shows that CD4 cell counts were 5% elevated in the 750 mg didanosine group at week 2, but had declined to 10% lower by week 24. In the 500 mg didanosine group, counts rose 2% at weeks 2 and 8, but had also dropped 10% below baseline by 24 weeks. In the AZT group, counts dropped continuously, ending up 23% lower by week 24]”

“CD4 lymphopenia <0.4 billion/L [i.e. < 400 cells per microliter] is rare in healthy individuals but in some subjects the CD4 levels are set at such a low value. In these individuals serial CD4 counts are stable [based on 7-10 measurements from four people]…Among other diseases primary immunodeficiency, tuberculosis, early acute phases of viral infections such as influenza, Dengue fever and even trauma can also cause CD4 depletion. Inverted CD4/CD8 ratios among the non-hospitalized controls are seen at 10% frequency, and even more frequently among seronegative homosexual men (27%)…[and] also in disease conditions with antigen overload such as frequently transfused patients with thalassaemia…only [!] about 1.4-3% of individuals in the healthy and homosexual seronegative control groups exhibit both abnormal features [low absolute CD4 count and inverted CD4/CD8 ratio]”

“CD4+ [immune cell] counts were higher in cases with KS [a skin cancer], lymphoma, HIV encephalopathy and wasting, compared with cases with Opportunistic Infections [but this does not match the theory that HIV attacks CD4 cells and causes immune suppression]”

“47 cases of AIDS were identified among the seropositive [IV drug using] subjects during the study period. The likelihood of developing AIDS was inversely related to the CD4 cell count at baseline...[but]...The principal finding was the slow rate of decline in CD4 lymphocyte counts in HIV-1 seropositive IVDUs over a 2.5 year period [and some cases of AIDS occurred at quite high CD4 cell counts]”

“In the group [of 10 asymptomatic HIV-positive hemophiliacs] switched to the very high purity [Factor VIII] concentrate there was no significant change of the CD4 cell counts over the 96-week follow-up period, whereas in the group continued on the intermediate purity concentrate [also 10 asymptomatic HIV-positive hemophiliacs], a highly significant decline was detected (p < .013) [indicates that CD4 cell counts are affected by the purity of blood products]”

“CD4 counts have been closely followed in [hemophiliac] patients treated with different [blood clotting] factor concentrates. Stabilization of counts and reversal of skin-test anergy have been reported following 24 months of therapy with Monoclate [a high purity blood clotting factor, with fewer immunosuppressive foreign proteins]”

“Cigarette smokers [from a group of 84 healthy black men and 79 healthy black women] had a significantly higher total white blood cell (WBC) count than nonsmokers. The cell counts for all cell types except monocytes were increased among smokers…CD4+ cells, CS [cigarette smokers] 1530 vs NS [non-smokers] 1281; CD8+ cells, CS 538 vs NS 443…[compared with a previous study of white smokers] White smokers had a significantly higher proportion of CD4+ cells [and] a slightly higher CD4:CD8 ratio…For whites…smoking 10 additional cigarettes per day increased the proportion of CD4+ cells by 1.2 percentage points. For blacks among whom smokers had a decrease in [the ratio of] CD4+ cells [compared to CD8+ cells], the same increment in cigarette consumption was associated with a decrease in the proportion of CD4+ cells by nearly 2 percentage points.”

“The CD4 T-cell numbers used in the analysis of the real data were adjusted to correct for fluctuations in an HIV free control group in time which were possibly the result of technical reasons [i.e. CD4 cell counts fluctuated significantly over time for unknown reasons yet if CD4 cell counts fluctuate in an individual this is given life or death significance]”

“An increased risk of HIV infection was associated with a low number of T4 [CD4] lymphocytes at first visit…Among the 13 seroconverters in whom T-lymphocyte subsets were measured at enrollment, only 2 had more than 1,000 T4 cells. This low number of T4 cells was the highest risk factor for HIV infection. [Note that this means that CD4 suppression PRECEDES HIV infection, yet HIV is supposed to be the killer of CD4 cells!]”

“some of the variation observed in the MACS data over time [CD4 counts and other measurements] was due at least in part to technical factors. First, the patterns of fluctuations were different at each center. In addition, the same whole blood sendout specimens yielded different results when analyzed in the four laboratories, and these differences closely paralleled the relative levels of the subsets for the homosexual seronegative [HIV-negative] men at the corresponding time periods…the HIV-seronegative homosexual men served as the primary control group. The T-cell values in this group suggest significant bias in the T-cell measurements over time [for example, for Center 2 the CD4 counts for HIV-negative homosexual men went steadily down over 8 visits, and for Center 3 the counts went steadily up for 8 visits]”

“The distribution of CD4+ cell counts in [HIV] seronegative smokers is shifted substantially higher than the distribution in seronegative non-smokers…CD4+ cell counts were significantly lower in non-smokers compared with smokers in the seronegative men, with a difference in the medians of 230 cells/µL…Median counts for seronegative men increased as packs of 20 smoked per day increased…Among seronegative smokers counts dropped on average 54 cells/µL within 6 months of quitting…Among those who started or resumed smoking counts rose on average 65 cells/µL in the [HIV-negative] controls.”

“A CD4 count below 200 was the single strongest predictor of the development of disease”

“The study population consisted of 108 smokers and 174 nonsmokers [all ‘caucasian’], with approximately equal numbers of men and women in each 10-yr age group…Cigarette smoking was associated with an increase in WBC [white blood cell] count…cigarette smokers had a small but significant increase in the proportion of CD4+ cells compared to nonsmokers. However, increasing age and female gender were also associated with a significant increase in percent CD4+ cells, as well as a decrease in percent CD8+ cells and an increased CD4+/CD8+ ratio. The association between cigarette smoking and increased CD4+ cells remained highly significant after controlling for age and gender…the percentage of CD4+ cells tended to increase with the number of cigarettes smoked per day”

“Further analysis for another 147 subjects showed that the 95% tolerance prediction for the CD4/CD8 ratio in health could be stated with 95% confidence as 0.6 to 5.0.”

“At baseline, the mean level of CD4+ cells among 750 seronegatives was 898 cells/mm-cubed and among 811 seropositives was 535…The mean level…among the 61 men who subsequently seroconverted [became HIV+] was 854…prior to the seroconversion visit and 651…on the visit after seroconversion, an average decline of 24%. [individual data is not provided, which probably shows that individual changes were all over the map]…[and, indeed] To our surprise, given that HIV infection results in depletion of CD4+ cells, less than 1% of the 51 seroconverters experienced a persistent negative slope (decreasing percent of CD4+ cells)”

“some healthy seropositive individuals lose a large proportion of their CD4+ lymphocytes, yet do not develop symptoms...Two patients followed at our medical center have had only 5% of their normal CD4+ cell number for over a year without any new symptoms. Thus, predictions on the development of opportunistic infections or cancers based solely on a decrease in CD4+ cells could be misleading.”

“We followed up HIV-seropositive subjects detected through the systematic screening of blood donations. 84 subjects had twice-yearly checks, including physical examination, CD4 count, blood count, erythrocyte sedimentation rate (ESR) check and HIV antigenemia check. Subjects at risk for HIV infection comprised 43 homosexual men, 16 bisexual men, 8 drug addicts, 10 heterosexual contacts with risk-factor partner, and 2 recipients of blood transfusions. Subjects also included five without known risk factors…None had AIDS at the first examination…At the end of follow-up, eight patients [with high ESR counts at the start of the study] (6 with AIDS) and only two [with low ESR counts] (one with AIDS) had a CD4 count <100 [per cubic millimeter]…An increased ESR in HIV-seropositive subjects seems to constitute a predictive marker of progression towards AIDS, before the decrease of the CD4 count.”

“tuberculosis itself depresses T-cell function and causes a reversed helper [CD4] : suppressor [CD8] T-cell ratio”

“[A] real T-helper [CD4] lymphopenia is only consistent with and not diagnostic of AIDS [even though it is now used to diagnose AIDS]; other diseases and some treatment regimens also can express a T-helper lymphopenia [deficiency], such as hospitalized non-AIDS IV drug abusers”

“The 53 patients studied included 15 homo- and 11 heterosexual men with chronic HBV [Hepatitis-B Virus] infection, as well as 11 homo- and 16 heterosexual men who were in apparent good health...Only 4 patients in this study had detectable anti-HIV [HIV antibodies] by ELISA...The mean [CD4/CD8] ratio was significantly lower in homosexual men, independent of HBV infection...Although 4 patients in this study had [HIV antibodies], the association of the abnormalities of T lymphocyte subsets [CD4/CD8] and NK [Natural Killer] activity with homosexuality remained significant after exclusion of these 4 patients from the data analysis [this paper does not consider the possibility that nitrite inhalants, almost exclusively marketed and used by homosexual men, could have affected the CD4/CD8 cell counts]”

“Primary tissue samples were obtained from 20 individuals previously diagnosed with AIDS or ARC. Of seven lymph node suspensions hybridized with the HTLV-III probe R3, six (86%) showed the presence of infected cells expressing HTLV-III RNA…Labeled cells were very rare, constituting <0.01% [1 out of 10,000] and, in some cases, <0.001% [1 out of 100,000] of the cell populations. Hybridization of probe R3 to peripheral blood mononuclear cells also resulted in labeling of very rare cells that represented HTLV-III-expressing cells. However, a lower percentage of the peripheral blood samples studied were positive for labeled cells (7 of 14, or 50%) as compared to lymph node.”

“Between April and October, 1984, anti-HTLV-III [HIV antibodies] developed in 16 patients with hemophilia A...[of whom] all but one had received a common batch [of clotting] factor VIII...a further eighteen patients received the implicated batch A...[but] have been negative for [HIV antibodies]...Lymphocyte subsets [CD4/CD8 cells] were investigated in 24 of the patients...the patients in whom [HIV antibodies] later developed had lower [CD4/CD8] ratios than those who did not seroconvert and the controls. The difference...just failed to reach statistical significance. In 1983 the absolute [CD4] cell numbers in those who subsequently seroconverted were significantly lower than those in the controls...The 15 patients who seroconverted used significantly more vials of batch A and also had a higher annual factor VIII consumption than the eighteen patients who did not seroconvert...Our finding in this study that T-helper-cell numbers and the helper/suppressor ratio did not change after infection supports our previous conclusion that the abnormal T-lymphocyte subsets [CD4/CD8 cells] are a result of the intravenous infusion of factor VII concentrates per se, not [HIV] infection”

“There was no characteristic change in the absolute numbers of T4+ (CD4) cells before and after seroconversion [in 11 subjects who became HIV-positive within a six month period]”

“The commonest cause of T-cell [CD4 cell] immunodeficiency worldwide is protein-calorie malnutrition…[in Developing Countries] the widespread distribution of parasitic infections with known immunosuppressive activity leading to opportunistic infections, and the coexistence of mulitple parasites in the same subject [person], make it difficult to identify patients with AIDS on the basis of the current epidemiologic criteria [e.g. the ‘Bangui’ definition] and immunologic aberrations [i.e. low CD4 cell counts or abnormal CD4/CD8 ratios]”

“38 patients with the acquired immunodeficiency syndrome (AIDS) were identified in Kinshasa, Zaire, during a 3 week period in 1983…Opportunistic infections were diagnosed in 32 (84%) patients, disseminated Kaposi’s sarcoma (KS) with opportunistic infection in 5 (13%) and disseminated KS along in 1 patient. Immunological characteristics of these patients were as reported for cases in the USA and Europe, but immunological abnormalities were also found in 6 controls with infectious diseases but no symptoms of AIDS……Patients with AIDS in Zaire demonstrated immunological abnormalities similar to patients in other parts of the world. However, several control patients with malaria and tuberculosis exhibited abnormal immunological test results as well, although none had cutaneous anergy. Tuberculosis, protein calorie malnutrition, and various parasitic diseases can all be associated with depression of cellular immunity.”

“we tested six asymptomatic asthmatics who were sensitive to mixed grass (positive skin test) with mixed grass extract, methacholine, and an antigen to which they were not sensitized (negative skin test). Levels of OKT4 [CD4] (helper T lymphocytes) were reduced in the peripheral blood immediately after the challenge with mixed grass extract, and remained low for at least 72 hours [note that low CD4 cell counts are supposed to be unique to AIDS by many accounts]”

“In answer to your letter of March 9, I would like to address some of the points you made. First, there is no evidence that the situation with HTLV is similar to EBV. On the contrary, the epidemiologic evidence shows a close association between disease and HTLV infection. EBV is ubiquitous. Second, I don’t understand why there is a problem with one virus causing “clonal inducer T-cell malignancies” and immunosuppressive disorders. In the cat system It’s been accepted for years (at least 10) that FeLV more often induces an immunosuppressive state than leukemia. The age of initial infection, route of exposure and whether there is repeat exposure are all apparent factors in the disease outcome of FeLV infection. If the T4 cells are the target of HTLV and this infection abrogates their function (as shown by M. Popovic, B. Dupont, A. Fauci and myself), then I can easily see that infection could lead to immunosuppression. Third, I’m not surprised that you have not found p19 expression on fresh cells of “AIDS” patients. It’s extremely rare to find fresh cells expressing the virus. As in the bovine system, cell culture seems to be necessary to induce virus. This is probably due to removal of inhibiting factors present in the patient. The antigens p24 and p19 are almost always detected simultaneously. Finally, we know now there are many variants of HTLV-I. We believe the cause of AIDS is a more highly cytopathic variant.”

“follow-up studies after booster immunization with tetanus toxoid revealed a significant decrease in the OKT4[CD4+]/OKT8[CD8+] ratios. In 4 of the 11 healthy volunteers, the OKT4/OKT8 ratio fell to 1 or less…The decrease in the OKT4/OKT8 ratio after vaccination was due to a reduction of OKT4+ cells in the peripheral blood of these donors…The results presented in this letter demonstrate that abnormal T-lymphocyte helper/suppressor ratios can be detected in healthy persons after immunization with a widely used antigen.”

“Ten patients (6 males and 4 females)...were studied during the acute...or convalescent phases of CMV[Cytomegalovirus]-mononucleosis..Analysis of the T lymphocyte subsets..indicated both relative and absolute reductions in the T helper [CD4] subset and simultaneous increases in the T suppressor [CD8] population...Recent studies suggest that a delicate balance exists between helper [CD4] and suppressor [CD8] T lymphocytes in the maintenance of immune homeostasis. Several disease states have been associated with alterations in this balance [not just HIV, even though an imbalance in CD4/CD8 cell counts is now considered, along with an HIV test, diagnostic for AIDS, at least in the USA]”