Cytomegalovirus seroconversion as a cofactor for progression to AIDS

OBJECTIVE: To study the impact of cytomegalovirus (CMV) seroconversion on HIV-1 disease progression. DESIGN: Follow-up of CMV-seronegative subjects enrolled in the French SEROCO/HEMOCO cohorts of HIV-infected subjects. METHODS: A total of 290 subjects were CMV-seronegative at enrolment in the cohort. Serological testing for CMV infection was done at enrolment and then every 6 months in CMV-seronegative subjects. The person-years method was used to calculate the incidence of CMV seroconversion. After adjustment for age, the CD4+ cell count at enrolment and the HIV exposure group in a Cox model, we studied CMV seroconversion as a time-dependent variable in progression to a CD4+ cell count below 200 x 10(6) cells/l and to clinical AIDS. RESULTS: Overall, 61 CMV seroconversions were observed. The overall incidence rate was 4.4 per 100 person-years [95% confidence interval (CI), 3.3-5.5]. The risk of progression to a CD4+ cell count below 200 x 10(6) cells/l was not increased in CMV seroconverters. However, the risk of progression to AIDS was increased two-fold in CMV seroconverters compared with subjects who remained CMV-seronegative [relative risk (RR) = 2.09; 95% CI, 1.16-3.74; P = 0.01]. CONCLUSION: This analysis of 61 CMV seroconversions, the largest study in the literature, confirms the impact of recent CMV infection on progression to AIDS.     

Both serum HIV type 1 RNA levels and CD4+ lymphocyte counts predict clinical outcome in HIV type 1-infected subjects with 200 to 500 CD4+ cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team

To evaluate HIV-1 RNA and CD4+ cell responses to therapy as predictors of clinical progression and to evaluate levels and trends of these markers prior to clinical failure, HIV-1 RNA measurements were retrospectively obtained on subjects who progressed to AIDS or death and a random sample of subjects who did not. Samples were taken from AIDS Clinical Trials Group Study 175, a randomized trial comparing nucleoside analog therapies in subjects with CD4+ cell counts of between 200 and 500 cells/mm3. HIV-1 RNA and CD4+ cell count independently predicted clinical progression. Risk of subsequent progression is best captured by the change to the last measured value for CD4+ cell count and the area under the curve minus baseline, a measure of viral replication over time, for HIV-1 RNA. Subjects who failed had lower CD4+ cell counts, greater rates of CD4+ cell decline, and higher HIV-1 RNA levels, but not greater rates of HIV-1 RNA increase than subjects who did not. Subjects who maintained more than 200 CD4+ cells/mm3 and fewer than 10,000 copies of HIV-1 RNA per milliliter had low risk of progression. During the first few months of therapy, treatments are best monitored by regular HIV-1 RNA and less frequent CD4+ cell measurements. Thereafter, both markers should be monitored on a similar schedule to identify rapidly declining CD4+ cell counts, or adverse levels of either. These results further delineate the prognostic significance of HIV-1 RNA and CD4+ cell count and should help to better define their utility in the practice setting.     

Human immunodeficiency virus type 1 p24 concentration measured by boosted ELISA of heat-denatured plasma correlates with decline in CD4 cells, progression to AIDS, and survival: comparison with viral RNA measurement

Human immunodeficiency virus type 1 (HIV-1) RNA and p24 antigen concentrations were determined in plasma samples from 169 chronically infected patients (median CD4 cell count, 140 cells/microL; range, 0-1500 cells/microL). p24 quantification involved heat-mediated immune complex dissociation and tyramide signal amplification-boosted ELISA, which has a diagnostic sensitivity similar to that of RNA quantification by a commercial polymerase chain reaction kit. In Cox's proportional hazard models adjusted for CD4 cell count, both RNA (P<.005) and p24 (P=.043) levels were significant predictors of progression to AIDS. Measurement of p24 was superior to measurement of RNA in the model for survival (P=.032 vs. P=.19). p24 level was a significant predictor of CD4 cell decline in models adjusted for CD4 cell counts and was superior or equivalent to RNA level, depending on the group analyzed. Stratification by CD4 cell counts at baseline showed that the superiority of p24 measurement was more pronounced at lower levels of CD4 cells (<200/microL). p24 level may be of interest as a simple and inexpensive predictive marker of disease progression.     

Heat-denatured human immunodeficiency virus type 1 protein 24 antigen: prognostic value in adults with early-stage disease

CD4(+) lymphocyte count and human immunodeficiency virus (HIV) type 1 RNA level are useful for determining when to initiate antiretroviral therapy but are not used widely in developing countries due to the high cost. Heat-denatured protein 24 (p24) antigen is an inexpensive assay that predicts disease progression among persons with advanced disease but has not been assessed among persons with early-stage disease. Plasma levels of heat-denatured p24 antigen were quantified in baseline study-visit specimens obtained from injection drug users enrolled in a longitudinal cohort study of HIV-1 infection. Of the 494 study participants (median initial CD4(+) lymphocyte count, 518 lymphocytes/mm(3)), 90 (18%) progressed to acquired immunodeficiency syndrome within 5 years. p24 antigen level correlated with both CD4(+) lymphocyte count (r=-0.34; P<.0001) and HIV-1 RNA level (r=0.55; P<.0001). p24 antigen level >5 pg/mL predicted disease progression, comparable with that of cutoff CD4(+) lymphocyte count <350 lymphocytes/mm(3) and HIV-1 RNA level >30,000 copies/mL. Heat-denatured p24 antigen level predicted subsequent clinical disease progression in early-stage HIV-1 infection and correlated with both CD4(+) lymphocyte count and HIV-1 RNA level.     

Predicting progression to AIDS: combined usefulness of CD4 lymphocyte counts and p24 antigenemia

PURPOSE: To investigate the combined usefulness of CD4 lymphocyte counts and human immunodeficiency virus type 1 (HIV-1) p24 antigen in predicting progression to the acquired immunodeficiency syndrome (AIDS). PATIENTS AND METHODS: CD4 lymphocyte counts and HIV-1 p24 antigen status were evaluated over a 4-year period in 518 HIV-1-seropositive men enrolled in the Multicenter AIDS Cohort Study in Chicago. RESULTS: Twenty-six percent (134 of 518) of the HIV-1-seropositive cohort had detectable p24 antigen during the study period. Men with p24 antigenemia experienced a more rapid decline in CD4 lymphocyte counts than men who were persistently p24 antigen-negative (p less than 0.01). Mean CD4 lymphocyte counts at first detection of p24 antigen were 406 and 455 cells/microL for men with incident and prevalent antigenemia, respectively. Antigen was detected in 61% (63 of 103) of the men who progressed to AIDS and in only 17% (71 of 415) of the men who did not (p less than 0.0001). The 4-year estimated cumulative AIDS incidence was 86%, 63%, and 21% for men with entry CD4 counts less than 200, 200 to 399, and 400 or more cells/microL, respectively. Presence of p24 antigenemia was strongly associated with more rapid disease progression within each of these CD4 groupings (p less than 0.0001). CONCLUSION: Our data indicate that p24 antigenemia can first be detected with moderate CD4 cell depletion, is associated with a more rapid decline in the CD4 lymphocyte population, and combined with CD4 lymphocyte counts is useful in identifying individuals at significantly greater risk of disease progression. Our findings provide important information for assessing HIV-1 disease prognosis over a 4-year period.     

Clinical progression in early and late stages of disease in a cohort of individuals infected with human immunodeficiency virus-2 in Guinea-Bissau

The aim of this study was to assess the rate of clinical progression to early and late stages of human immunodeficiency virus-2 (HIV-2) infection. CD4 cell counts and other potential prognostic markers for disease progression were also evaluated. In January 1990 an open prospective cohort of police officers in Guinea-Bissau was initiated with yearly serological and clinical follow-up. Follow-up ended in June 1998. Symptoms were classified according to the World Health Organization staging system. The analysis included 148 HIV-2-seropositive subjects and 177 HIV-seronegative controls. 25 of the HIV-2-positive individuals were seroconverters (seroincident cases). The progression rate to stage 3 of HIV-2-positive subjects in stage 1+2 was 8.6/100 person-years (py) (rate ratio 6.2 compared with HIV-negative controls, 95% confidence interval 2.7-14.2, p < 0.001), and the progression rate to stage 4, i.e. acquired immunodeficiency syndrome (AIDS), was 2.1/100 py. HIV-2-positive people in stage 3 at inclusion progressed to AIDS at a rate of 16.9/100 py. CD4% < or = 20 was found to be a significant prognostic marker for progression to stage 4, both from stage 1+2 and from stage 3. The clinical progression in this cohort of HIV-2-infected subjects was generally lower than that in HIV-1-positive cohorts.     

Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study

We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS Cohort Study (MACS) who were selected to reflect the full spectrum of rates of HIV-1 disease progression. A mean of 10 serial samples per donor were evaluated by a laboratory-validated, commercially available assay to determine phenotypic coreceptor use. A total of 52% of men had dual- or mixed-tropic HIV-1 detected at 1 or more of the time points tested. Use of X4 by HIV-1 was detected more frequently among men who developed AIDS (defined as a CD4(+) T cell count of <200 cells/muL and/or an AIDS-defining illness) < or =11 years after seroconversion than among those who did not (P = .005), as well as among men who exhibited a total T cell count decline (i.e., a CD3(+) inflection point), compared with those who did not (P = .03). For men in whom both X4 virus and an inflection point were detected, emergence of X4 virus preceded the inflection point by a median of 0.83 years. The median CD4(+) T cell count at first detection of X4 viruses before the onset of AIDS was 475 cells/microL. We conclude that HIV-1 variants that used X4 frequently emerged at high CD4(+) T cell counts and may contribute to the decrease in T cell numbers during late HIV-1 infection.     

Serum HIV-1 p24 antibody, HIV-1 RNA copy number and CD4 lymphocyte percentage are independently associated with risk of mortality in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group

OBJECTIVE: The role of HIV-1 antibody in modulating disease progression must be assessed in the context of other immune and viral load markers. We evaluated the association between HIV-1 p24 antibody, HIV-1 RNA, immune complex-dissociated (ICD) p24 antigen, CD4 cell percentage, and mortality in a cohort of 218 HIV-infected children enrolled in a trial of intravenous immunoglobulin prophylaxis of bacterial infections. METHODS: CD4 cell percentage was measured and sera collected and stored at baseline and every 3 months on study (1988-1991). Stored sera were assayed for HIV-1 p24 antibody, HIV-1 RNA, and ICD p24 antigen. Mortality was recorded during the trial and updated through 1996 (mean total follow-up, 6.3 years). RESULTS: Eighty-one (37%) children died; probability of mortality for children with baseline HIV-1 p24 antibody concentrations of undetectable (< 1), 1-4, 5-124, and > or = 125 reciprocal titer units (RTU) was 61, 50, 24, and 10%, respectively. A 3.5-fold increase in the relative risk (RR) of death [95% confidence interval (CI), 2.2-5.5] was observed among children with baseline HIV-1 p24 antibody concentration < 5 RTU compared with > or = 5 RTU. In multivariate analyses, p24 antibody, HIV-1 RNA, and CD4 cell percentage but not ICD p24 antigen were independently associated with mortality; the RR of death increased by 1.7 (95% CI, 1.3-2.1) for each log10 decrement in baseline HIV-1 p24 antibody. CONCLUSIONS: HIV-1 p24 antibody, HIV-1 RNA and CD4 cell percentage independently predict mortality amongst infected children. Whereas CD4 cell percentage provides an estimate of the general degree of immune suppression, HIV-1 p24 antibody could provide an easily obtained, inexpensive assessment of CD4 cell function and could augment prognostic information provided by CD4 cell count and viral load for clinical management of infected children.     

Clinical correlation of the immunological markers of HIV infection in individuals from Thailand.

OBJECTIVE: To evaluate the usefulness of T-cell subsets, beta-microglobulin (B2M), p24 antigen and anti-p24 antibodies as differentiating and prognostic markers in HIV-infected Thai patients. DESIGN: Sixty-one HIV-infected patients in various stages of disease (six AIDS, three AIDS-related complex, 34 persistent generalized lymphadenopathy and 18 HIV-asymptomatic) were followed prospectively for 2 years. Patients were examined and immunological markers assessed every 6 months at least. Any HIV-related complications were treated symptomatically and clinical staging was re-evaluated at each visit. Due to financial constraints, none of the patients were given antiretroviral drugs. METHODS: T-cell subsets were enumerated by indirect immunofluorescence using OKT4 or OKT8 for T-helper and T-suppressor cells, respectively. beta 2M and p24 antigen were quantified by enzyme-linked immunosorbent assay and anti-p24 antibodies were by immunoblot assay. RESULTS: Our preliminary study revealed that the decrease in CD4+ T-cells or anti-p24 titre and the increase in p24 antigen or beta 2M correlated well with disease staging, as defined by the Centers for Disease Control. Absolute number and percentage of CD4+ T-cells, absolute number of CD8+ T-cells, beta 2M level and p24 antigen and anti-p24 antibody levels at entry could be used as reliable prognostic markers for HIV progression. The combination of p24 antigen with the number of CD4+ T-cells substantially increased the prognostic value, compared with either used alone. CONCLUSIONS: The annual rate of clinical progression from asymptomatic to symptomatic HIV infection in our study was 6.8%. The results we obtained in this preliminary study may be used as baseline data for planning future therapeutic interventions in Asian patients.     

Effects of passive immunization in patients with the acquired immunodeficiency syndrome-related complex and acquired immunodeficiency syndrome.

Infection with the human immunodeficiency virus type 1 (HIV-1) is usually followed by a vigorous immune response that temporarily protects against disease progression. After a variable asymptomatic period, acquired immunodeficiency syndrome (AIDS)-related complex (ARC) and AIDS develop in most infected individuals. We have demonstrated that healthy HIV-1-infected individuals have neutralizing antibodies and a high titer of antiviral antibodies. In contrast, AIDS patients have undetectable levels of neutralizing antibodies, low titers of antiviral antibodies, and, frequently, HIV p24 antigenemia. These observations prompted us to attempt passive immunization in ARC and AIDS patients. Ten consistently viral-antigen-positive patients (mean, greater than 6 months) were treated, resulting in sustained clearance of p24 antigen. Patients either maintained or increased their antiviral antibody titers. The raised titers result from increased antibody synthesis by the recipients. Circulating CD4+ cell counts were unchanged after 2 months. By the third month none of these patients remained in hospital. As this treatment was of minimal toxicity, it merits wider evaluation in ARC and AIDS patients.     

Persistent immune activation in HIV-1 infection is associated with progression to AIDS

BACKGROUND: HIV-1 infection is characterized by chronic generalized CD8 and CD4 T cell hyperactivation, the biological effect of which is not understood. OBJECTIVE: To study the relation between chronic immune activation and CD4 T cell depletion in HIV-1 infection. DESIGN: Prospective cohort study among participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who have a known seroconversion date (n = 102). METHODS: CD4 and CD8 T cell activation marker expression was analysed by FACScan before and after seroconversion (1 and 5 years after seroconversion); T cell proliferation and T cell numbers were also measured. Cox proportional hazard analyses were used to study the predictive value of these parameters for progression to AIDS. RESULTS: Preseroconversion low CD4 T cell numbers or elevated levels of CD4 T cell activation were associated with increased risk for development of AIDS after HIV-1 seroconversion. Progression to AIDS was associated with loss of both CD4 and CD8 naive T cells. The predictive value of CD8 T cell activation was confirmed and, in addition, in the course of infection low CD4 T cell counts and increasing proportions of dividing CD4 T cells, dividing CD8 T cells or elevated CD4 T cell activation marker expression became independent predictors of progression to AIDS. CONCLUSIONS: Increased T cell activation has predictive value for HIV-1 disease progression even before seroconversion. These data support the hypothesis that persistent hyperactivation of the immune system may lead to erosion of the naive T cell pool and CD4 T cell depletion.     

Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group

OBJECTIVE: To describe the spontaneous course, before the introduction of highly active antiretroviral therapy (HAART), of HIV-1 RNA during the AIDS-free period of the disease. To assess the predictive value of changes in HIV-1 RNA levels. DESIGN: A total of 330 patients with a known date of infection followed in the SEROCO cohort. METHODS: HIV-1 RNA levels (threshold, 200 copies/ml) were evaluated from 2243 frozen sera obtained from enrolment until the onset of AIDS or until February 1996. Lowess curves were used to describe the variations of viraemia during follow-up. A Cox regression model was used to assess the predictive value of early and updated CD4 cell count and viral load. RESULTS: In addition to a lower early viral load, patients who remained AIDS-free had, on average, a longer period of viral load decrease after infection (36 versus 18 months), followed by a slower viral load increase compared with those who progressed to AIDS. A true plateau-phase after the seroconversion period, lasting approximately 4 years, was identified only in patients who remained AIDS-free for at least 90 months. In multivariate analysis, both early viral load and later changes were significant predictors of progression to AIDS. A decrease in the CD4 cell count to less than 200 cells/microl and the onset of a group B condition remained significant predictors of progression. CONCLUSION: Our study extends to the early post-seroconversion phase the prognostic value of extracellular HIV-1 RNA levels. Moreover, our data suggest that, in most HIV-infected individuals, a progressive loss of control of viral replication arises during the early years of HIV-1 infection.     

HIV／AIDS患者血浆病毒载量及外周血T淋巴细胞亚群的变化

目的：观察国内HIV／AIDS患者血浆病毒载量和外周血CD4^ 、CD8^ T淋巴细胞的变化，探讨这些变化的临床意义。方法：选择未经抗病毒治疗的HIV／AIDS患者124例，用bDNA法检测血浆病毒载量，并用流式细胞仪检测外周血CD4^ 、CD8^ T淋巴细胞。结果：AIDS患者的血浆病毒载量明显高于HIV感染者，血浆病毒载量与CD4^ 细胞计数呈显著负相关，但其最高峰位于CD4^ 细胞计数100／μl处，然后随着CD4^ 细胞计数的下降而减少。CD4^ T细胞计数为AIDS组＜HIV组＜正常对照组：HIV感染者的CD8^ T细胞计数显著高于正常组和AIDS组，而AIDS患者CD8^ T细胞数则随着CD4^ T细胞减少而下降。结论：血浆病毒载量随着疾病进展而显著升高，但在疾病晚期则有所降低。外周血CD4^ T细胞计数随着疾病的进展而进行性减少；CD8^ T细胞计数在感染早期显著升高，进入晚期则减少。在评价HIV感染者和AIDS患者病情时，应结合病毒载量、CD4^ 、CD8^ T细胞计数综合分析。     

Association between HIV Type 1-specific T cell responses and CD4+ T cell counts or CD4+:CD8+ T cell ratios in HIV Type 1 subtype B infection in China

CD4+ T cell counts and CD4+:CD8+ T cell ratios represent key determinants of HIV disease progression and infectivity. However, the relationship between the HIV-1-specific cytotoxic T lymphocyte (CTL) response and these determinants has not been elucidated for all HIV-1B and HIV-1C proteins. In the present study, virusspecific T cell responses to HIV-1B and HIV-1C proteins were analyzed with interferon gamma (IFN-gamma) enzyme- linked immunospot (ELISpot) assays using synthetic overlapping peptides corresponding to naturally occurring HIV-1B and HIV-1C consensus sequences. For Gag/Gag p24/Gag p17, a correlation between T cell responses and CD4+ T cell count in HIV-1 clade B and clade C was seen: elevated T cell response resulted in higher CD4+ T cell production. A statistically significant correlation between the Pol-specific T cell response and CD4+ T cell counts was also found in HIV-1 subtype C. For all HIV-1B and HIV-1C proteins, a correlation between the HIV-1-specific T cell response and CD4+:CD8+ T cell ratios was found for Tat and Pol proteins. CD4+ T cell counts in patients with Tat and/or Rev T cell response were higher than in patients without Tat and/or Rev T cell response. We suggest that this correlation within HIV-1B and HIV-1C Gag p24/Gag p17 responses makes the Gag p24/Gag p17 region a potential vaccine candidate and that HIV-1-specific CTL epitopes toward Pol are important in controlling HIV-1 infection; we emphasize that future vaccination strategies should include these early antigens, Tat and Rev.     

Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters

OBJECTIVES: To identify factors associated with sustained undetectable viraemia after HIV-1 seroconversion in treatment-naive patients, and to describe concomitant CD4 cell count progression. METHODS: Seroconverters enrolled in CASCADE were assumed to control viraemia if at least two consecutive viral load measurements were < 400/500 copies/ml without treatment. Factors associated with undetectable viraemia were identified through a logistic regression. A joint model was used to describe simultaneously the CD4 cell count progression during and after that period and to identify factors associated with sustained undetectable viraemia. RESULTS: Of 2176 seroconverters, 145 (6.7%) spontaneously controlled viraemia. Women were more likely than men to achieve undetectable viraemia [adjusted odds ratio (OR), 2.12; 95% confidence interval (CI), 1.49-3.12] unlike patients who reported a symptomatic primary infection (adjusted OR, 0.58; 95% CI, 0.36-0.94). AIDS and death rates were significantly lower in patients achieving undetectable viraemia than in the others. The median period of undetectable viraemia was 11.2 months; on average, CD4 cell counts remained stable during that period, and decreased with a mean rate of 5 cells/microl per month thereafter. High CD4 cell count at the beginning of undetectable viraemia and non-symptomatic primary infection favoured the preservation of undetectable viraemia. CONCLUSION: A small proportion of seroconverters appeared to be able to control HIV viraemia spontaneously, mostly those without seroconversion illness and within a few years following seroconversion; this is associated with the benefits of slower CD4 cell count decline and improved long-term prognosis. Such persons should be targeted for in depth investigation.     

Decline in CD4+ cell numbers reflects increase in HIV-1 replication

Changes in CD4+ cell numbers were studied in relation to the presence of HIV-1 antigen (HIV-1-Ag) in serum from homosexual men followed prospectively. During 30 months of follow-up the mean CD4+ cell number (x 10(9) per liter) was stable in 134 at entry HIV-1 antibody (HIV-1-Ab) seropositives, who remained HIV-1-Ag negative (from 0.59 to 0.62) and declined in 38 at entry HIV-1-Ab seropositives who were persistently HIV-1-Ag positive (from 0.43 to 0.34). In sera of 9 of 65 HIV-1-Ab seroconverters HIV-1-Ag was detected only once, 3 months before or concomitantly with antibody seroconversion. Another 11 men became persistently HIV-1-Ag positive with antibody seroconversion or 2-6 weeks thereafter. A decline in CD4+ cell numbers was seen between 6 months before and the moment of HIV-1-Ab seroconversion, independently of duration and level of antigen expression. This indicates initial HIV-1 replication in both HIV-1-Ag negatives and positives. Following antibody seroconversion, HIV-1-Ag negatives had higher CD4+ cell numbers than HIV-1-Ag positives. Similarly to those who were HIV antigenemic from entry of the study, the HIV-1-Ab seroconverters who concomitantly with seroconversion or shortly thereafter became HIV-1 antigenemic showed a steady and significant (p = 0.01) decline in CD4+ cell numbers. In those who remained HIV-1-Ag negative after antibody seroconversion, CD4+ cell numbers were stable during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immune activation markers and AIDS prognosis.

Four assays for serum levels of cellular products of immune activation were examined as prognostic markers for AIDS in a prospective study of asymptomatic HIV-seropositive homosexual men. Baseline serum values of beta 2-microglobulin (beta 2M), neopterin, soluble CD8 (sCD8), and soluble interleukin-2 receptor (sIL-2R) for 185 men were examined univariately and multivariately as predictors of AIDS during 36 months of follow-up. Thirty-three cases of AIDS (18%) were diagnosed during the follow-up period. All four assays correlated highly with each other (r = 0.48-0.63), and all four were good univariate predictors of AIDS and comparable to CD4 lymphocyte count. beta 2M, neopterin, and sCD8 predicted AIDS independently of both CD4 count and HIV p24 antigen or p24 antibody in multivariate analysis. Within the range of CD4 count 200-499 x 10(6) cells/l, an immune activation marker used in combination with an assay for p24 antigen identifies those at 3-6% risk of AIDS over 36 months (low risk on both assays) and those at 63-86% risk (high risk on both assays). These results can be used to guide physicians and patients making decisions about treating asymptomatic HIV infection with zidovudine in individuals with CD4 lymphocyte count of 200-499 x 10(6) cells/l.     

Lymphoproliferative response to HIV type 1 p24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection.

To establish immunologic correlates of progression to AIDS in long-term survivors of HIV-1 infection, HIV-1-specific T cell-mediated responses, together with T cell reactivity to recall antigens, were studied in frozen samples collected after 5 and 8 years of documented HIV-1 infection. Eight of 21 homosexual men, who remained asymptomatic and maintained CD4+ T cell numbers >400 cells/microl for 9 years of HIV-1 infection, progressed to AIDS (CDC 1993 definition) within 12.5 years of infection (late progressors, LPs). The remainders showed minimal deterioration of immune parameters (long-term nonprogressors, LTNPs). CD4+ T cell numbers and T cell function measured at years 5 and 8 of follow-up were comparable in the two groups. At both time points responses to recall antigens did not significantly differ between the two groups, although a significant decline of lymphoproliferative responses to Candida and tetanus toxoid was observed in LPs. Circulating HIV-1-specific cytotoxic T lymphocyte precursors were found in broad frequency ranges in both LPs and LTNPs and, similarly, no significant differences were found in comparing the breadth of serum neutralizing activity against heterologous HIV-1 primary isolates. In contrast, lymphoproliferative responses to p24gag, but not p17gag or gp160env, were detected only in LTNPs and were totally absent in LPs at both time points (p < 0.01). Our data suggest that the presence of circulating p24-specific CD4+ T cells may reflect effective viral control and be predictive of subsequent favorable clinical course in long-term asymptomatic individuals.     

Persistently negative HIV-1 antibody enzyme immunoassay screening results for patients with HIV-1 infection and AIDS: serologic, clinical, and virologic results. Seronegative AIDS Clinical Study Group

OBJECTIVE: To describe persons with HIV infection and AIDS but with persistently negative HIV antibody enzyme immunoassay (EIA) results. DESIGN: Surveillance for persons meeting a case definition for HIV-1-seronegative AIDS. SETTING: United States and Canada. PATIENTS: A total of eight patients with seronegative AIDS identified from July 1995 through September 1997. MAIN OUTCOME MEASURES: Clinical history of HIV disease, history of HIV test results, and CD4 cell counts from medical record review; results of testing with a panel of EIA for antibodies to HIV-1, and HIV-1 p24 antigen; and viral subtype. RESULTS: Negative HIV EIA results occurred at CD4 cell counts of 0-230 x 10(6)/l, and at HIV RNA concentrations of 105,000-7,943,000 copies/ml. Using a panel of HIV EIA on sera from three patients, none of the HIV EIA detected infection with HIV-1, and signal-to-cut-off ratios were < or = 0.8 or all test kits evaluated. Sera from five patients showed weak reactivity in some HIV EIA, but were non-reactive in other HIV EIA. All patients were infected with HIV-1 subtype B. CONCLUSIONS: Rarely, results of EIA tests for antibodies to HIV-1 may be persistently negative in some HIV-1 subtype B-infected persons with AIDS. Physicians treating patients with illnesses or CD4 cell counts suggestive of HIV infection, but for whom results of HIV EIA are negative, should consider p24 antigen, nucleic acid amplification, or viral culture testing to document the presence of HIV.     

Comparative humoral responses to HIV-1 p24gag and gp120env in subjects from East Africa and the UK.

We compared 1616 sera from HIV-1-infected subjects and matched HIV-negative local controls in Uganda, Kenya and the UK. Sera were screened for specific antibody to HIV-1 p24 Gag and gp120 Env proteins and for p24 antigenaemia. In contrast to the UK, the majority of African HIV-1-infected subjects maintained detectable anti-p24 antibodies. However, lower reactivity of anti-p24 was observed in African AIDS patients, compared with those with asymptomatic HIV-1 infection. This reduction in anti-p24 reactivity with more advanced clinical stage was less marked in African HIV-1 infection than in the UK. Correspondingly, p24 antigenaemia was more common in patients with AIDS from the UK than in African patients (65 versus 4%). Reductions in anti-gp120 reactivity were observed in African AIDS patients, compared with the asymptomatic group. However, median reactivity of anti-gp120 in UK patients remained unchanged in both asymptomatic and AIDS subjects. The differences in humoral response to p24 and gp120 between Africa and the UK are semi-quantitative rather than qualitative and could be explained by initial higher antibody response to HIV-1 in African subjects.