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Background: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. Objective: To examine postulated associations of genetic alleles with HIV-1 disease progression. Design: Meta-analysis of individual-patient data. Setting: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. Patients: Patients with HIV-1 infection who were of European or African descent. Measurements: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. Results: Both the CCR5-delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(sub 10) copies/mL and 0.14 log(sub 10) copies/mL; P < 0.05 for both). Having the CCR5-delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3' A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). Conclusions: The CCR5-delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3' A homozygosity carried no such protection.

It seems unlikely that HIV causes immunosuppression directly by killing T cells. This is the most common theory regarding HIV-induced immunosuppression, but many studies have provided data contradicting this view. HIV is present in relatively low levels in blood and the immune system appears capable of regenerating T cells faster than the virus could reasonably kill them. It is estimated that 1% to 2% of the T cell population could be replaced daily, which is 10 to 20 times the rate that they would be depleted by HIV. It seems more likely that some type of immune dysfunction is responsible for producing AIDS.

Low levels of CD69 antigen expression in T lymphocytes, following stimulation, may be an indicator of immunologic problems in HIV-positive people. Researchers analyzed the levels of CD69 expression in T lymphocytes isolated from the blood of 25 HIV-positive and 12 HIV-negative people. The numbers and percentages of certain kinds of T lymphocytes expressing CD69 before stimulation were similar in HIV-positive and HIV-negative people. However, the percentage of certain kinds of T lymphocytes that expressed CD69 after stimulation was higher in HIV-negative people than in HIV-positive people. The factors used to stimulate the lymphocytes were antigens from different viruses, including the gp120 HIV antigen, and chemicals that trigger cell division. The gp120 antigen reduced expression of CD69 in certain T cells from HIV-negative people.

The concentration of HIV-infected cells in the circulating blood appears to remain constant in HIV-positive individuals though there are significant differences between those who rapidly develop AIDS and those who develop AIDS later. The HIV DNA concentration in blood samples from 28 participants was evaluated after they became HIV positive and again after five years. The patients were classified according to how quickly they developed symptoms of AIDS. Nine patients were classified as rapid progressors, nine as intermediate progressors and 10 as non-progressors. There was very little change in HIV DNA concentrations during the course of the study in all patients. However, those classified as non-progressors had the lowest concentrations of HIV DNA at the beginning of the study. Because the number of infected cells increases only slightly over time, it appears that a failure to suppress viral reproduction develops during the course of infection. Antiretroviral therapy is important for all HIV-positive patients regardless of HIV DNA concentrations.

Detecting HIV-1 more than six months before the appearance of antibodies against HIV-1 may not be possible. Researchers conducted polymerase chain reaction (PCR) and HIV-1 isolation tests on 138 antibody-negative and 41 antibody-positive blood samples from 41 homosexual men who became HIV-positive during a six-year study. They also tested a similar number of samples from HIV-negative homosexuals and from blood donors without risk factors for HIV infection to evaluate test reliability. In 38 of the 41 HIV-positive men, no virus could be detected before the first positive antibody test. In three cases, samples collected six months prior to becoming HIV-positive were positive in PCR and isolation tests. Overall, 88% of the 41 samples collected after the men became HIV-positive were positive on PCR tests and 65% were positive on isolation tests. After repeated testing, four of the HIV-negative homosexuals were determined to be HIV positive. It seems likely that HIV antibodies usually appear within six months of infection.

An expanded case definition for AIDS may more than double the number of HIV-positive individuals who are classified as having AIDS. The 1987 Centers for Disease Control (CDC) AIDS case definition may be expanded to include HIV-positive individuals with less that 200 CD4 T-cells per cubic millimeter of blood. The expanded case definition and two other expanded definitions of AIDS involving other T-cell subsets were used to classify 762 HIV-positive homosexual and bisexual men who were HIV-positive in 1984. Implementation of any one of the expanded definitions of AIDS in mid-1991 would have more than doubled the number of living HIV-positive individuals with AIDS. The proposed CDC definition would have increased the number of living HIV-positive individuals with AIDS in mid-1991 by 212%. The other two expanded case definitions would have increased this number by 266% and 272%.

The polymerase chain reaction (PCR) is a new technique in which low levels of genetic material are amplified to large quantities so that they can be studied. PCR is used to detect low levels of HIV (human immunodeficiency virus) in individuals who do not have detectable levels of HIV antibodies (based on the commonly used antibody test). The significance of positive PCR results in HIV-negative (seronegative) men is controversial, and the relation between such findings and the epidemiology of HIV infection is uncertain. An analysis of the results of the PCR reaction was performed with 324 men from the San Francisco Men's Health Study; 105 men were exclusively heterosexual and 219 were homosexual or bisexual. None of the men had detectable antibodies to HIV on standard tests. The frequency of positive PCR reactions between the two groups was compared and the risk factors for infection among the homosexual men were evaluated. Approximately 8.6 percent of the samples were weakly positive by the PCR reaction, but none were definitely positive. This finding occurred to the same level in men who had homosexual contact and were at risk for developing infection and in heterosexual men who were not at risk. These findings demonstrate that PCR testing does not provide evidence for the existence of a group of homosexual men with very low levels of virus. In addition, the results do not provide any indication that HIV can exist in low levels, as might occur in cases of latent infection (one that did not fully develop) or viral exposure without infection. (Consumer Summary produced by Reliance Medical Information, Inc.)

Cell-mediated immune responses are deficient in individuals infected with the human immunodeficiency virus (HIV), and the deficiency is progressive. Two clinical markers of the progression of HIV disease, antibody to the p24 core protein of HIV and neopterin concentrations in the blood, were studied in terms of their relationship to the outcome of HIV disease. Using data from a large population-based survey, 238 HIV-seropositive homosexual men were studied. Antibody levels to p24 core protein were determined, levels of CD4 cells were measured, and the concentration of neopterin in the blood was determined. Both antibody to p24 and the concentration of neopterin in the blood were found to be predictive of the development of AIDS as long as 54 months prior to its development. Specifically, low antibody levels and high levels of neopterin were independently and strongly related to poor outcome. This is consistent with the hypothesis that the intensity of the initial immune response to HIV (as measured by antibody levels) and the degree of immune response over time (measured by concentration of neopterin in the blood) are both important factors in determining disease outcome, independent of each other. About 60 percent of those with low antibody levels and high levels of neopterin developed AIDS over the 54 months, as compared with only 34 percent of patients who had either low antibody levels or high concentrations of neopterin in the blood. Fewer than 10 percent of those with high antibody levels and low neopterin concentrations developed AIDS during the period. It is suggested therefore that antibody and neopterin levels are independent measures that predict the outcome of HIV infection, but that they affect outcome in an interactive way. (Consumer Summary produced by Reliance Medical Information, Inc.)

The human immunodeficiency virus (HIV) is the causative agent of AIDS. HIV attacks and destroys immune system cells called CD4+ lymphocytes that are essential for fighting infection. One of the characteristic features of patients with AIDS is low numbers of CD4+ cells in the blood. It is well established that there is typically a delay of several years between the time of exposure to HIV and the development of AIDS. However, it is not known whether all people with HIV infection will eventually develop AIDS: in a recent study, only 54 percent of the patients who had HIV infection for 11 years had developed AIDS. It is not known why some people with HIV infection develop AIDS sooner than others, and why some appear to remain free of AIDS even though they have HIV infection. To address this issue, 24 men who had been infected with HIV for at least five years (average duration, 9.1 years) and had not developed symptoms of AIDS were examined. The results of blood tests performed on these patients were compared with those from 14 patients with AIDS and 24 without HIV infection. The patients with AIDS had very low numbers of CD4+ cells, while those with HIV infection without symptoms of AIDS had CD4+ cell counts of at least 400 cells/mm3, close to the normal range. However, the number of CD8+ lymphocytes was twice as high in the HIV patients who did not have symptoms of AIDS as in those with AIDS and those without HIV infection. Also, the HIV patients who did not have symptoms of AIDS had significantly higher blood levels of antibodies against HIV than those who had AIDS. These findings suggest that high levels of antibodies against HIV and high numbers of CD8+ cells may delay the development of AIDS in patients with HIV infection. Further studies are needed to test and verify these findings. (Consumer Summary produced by Reliance Medical Information, Inc.)

The polymerase chain reaction (PCR), a technique used to analyze genetic material, can be used to detect extremely small amounts of the human immunodeficiency virus type-1 (HIV-1). In fact, by analyzing DNA, PCR can detect the presence of the virus in individuals who do not seem to be infected, as indicated by the negative results of blood tests used to identify antibodies to HIV-1 (seronegative individuals). The sensitivity, specificity and accuracy of PCR testing were analyzed in five laboratories which were experienced in PCR techniques. All the laboratories used the same blood samples, which were obtained from 105 HIV-1 seronegative individuals who did not have any of the risk factors for HIV infection, such as homosexuality, hemophilia, intravenous drug use, and prostitution, and from 99 homosexual or bisexual men who were seropositive (that is, tested positive for antibody to HIV). The average sensitivity (being able to detect the presence of the virus) was 99 percent, with the range of sensitivity among the five laboratories ranging from 98 to 100 percent. The average specificity (the validity of detection) was 95 percent, with a range of 90 to 100 percent. The percentage of false-positive results (detected as positive, but really negative) was 2 percent, and the percentage false-negatives (detected as negative, but really positive) was 0.8 percent. Approximately 3 percent of the cases were misclassified due to laboratory error, such as specimen mix-up or carrying over results from one specimen to another. This study demonstrates that the PCR test had low specificity rates and high rates of false-negative results in some laboratories. Uniform results were not obtained in laboratories experienced in PCR techniques. The authors conclude that standardization of PCR testing must be achieved before this technique can be used as a routine test to determine the presence of HIV-1. Until then, PCR results should be interpreted with caution. (Consumer Summary produced by Reliance Medical Information, Inc.)

The objective of AIDS research is to understand how the human immunodeficiency virus (HIV) causes deterioration of the immune system. A decline in the number of helper T lymphocytes is seen, which leads to defective cell-mediated immune responses. This allows opportunistic infections to develop. It is known that the virus enters into cells via the binding of a protein in the outer layer of the virus, known as gp120, to a molecule, known as CD4, on T lymphocytes and other immune cells. This process kills the T lymphocytes, which leads to impaired immunity. However, there are other theories concerning how the interaction of the virus and the T cells causes disease. One of these theories is the panergic imnesia hypothesis, which states that the interaction causes generalized stimulation of T cells, disrupting critical immunologic regulatory mechanisms and leading to impaired immunity. The uncontrolled lymphocyte stimulation is called panergy. Clinical symptoms of panergy include an autoimmune response, (an immune response to normal components of cells), lymphadenopathy (hyperimmune reaction in the lymph nodes), and high levels of immunoglobulin, or antibody molecules, in the blood. The immune system cannot respond to other stimuli because the activated T cells cannot be activated further. The state of chronic activation interferes with the development of memory cells (imnesia), leading to a loss in the total number of cells. It is felt that therapeutic strategies should include: those that avoid immune stimulation; inhibition of factors which stimulate the immune system; blockage of gp120 from binding to CD4; and inhibition of the signal that is generated by CD4. (Consumer Summary produced by Reliance Medical Information, Inc.)