Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans.

CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G-->A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f<1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP.

Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring.

To compare electronically monitored (MEMS) with self-reported adherence in drug users, including the impact of adherence on HIV load, we conducted a 6-month observational study of 67 antiretroviral-experienced current and former drug users. Adherence (percentage of doses taken as prescribed) was calculated for both the day and the week preceding each of 6 research visits. Mean self-reported 1-day adherence was 79% (median, 86%), and mean self-reported 1-week adherence was 78% (median, 85%). Mean MEMS 1-day adherence was 57% (median, 52%), and mean MEMS 1-week adherence was 53% (median, 49%). One-day and 1-week estimates were highly correlated (r>.8 for both measures). Both self-reported and MEMS adherence were correlated with concurrent HIV load (r=.43-.60), but the likelihood of achieving virologic suppression was greater if MEMS adherence was high than if self-reported adherence was high. We conclude that self-reported adherence is higher than MEMS adherence, but a strong relationship exists between both measures and virus load. However, electronic monitoring is more sensitive than self-report for the detection of nonadherence and should be used in adherence intervention studies.

Tampons as a self-administered collection method for the detection and quantification of genital HIV-1.

OBJECTIVE: To assess the detection and quantitation of HIV-1 from tampon eluents in comparison with cervicovaginal lavage (CVL) and plasma specimens from the same women. METHODS: Ninety-seven tampon, 105 CVL, and 104 plasma specimens from 105 HIV-1 seropositive women were analyzed using Version 3 of the Chiron bDNA assay, with sensitivity of 50 HIV-1 RNA copies/ml. Data analyses used McNemar's test, Wilcoxon signed rank test, and Mantel--Haenszel chi-squared and odds ratios with 95% confidence intervals to assess differences in proportions. RESULTS: In women for whom both plasma and genital specimens were available, HIV-1 was detected less frequently in genital specimens: [tampons (33/97, 34%) and CVL (48/104, 46%)] than plasma specimens (86/104, 83%) (P < 0.001 for both plasma versus tampon and for plasma versus CVL). However, the proportion of genital specimens with detectable virus did not differ significantly by collection method (P = 0.14). Among women with detectable virus using both collection methods (n = 23), viral load was similar for tampon eluents (median, 355 copies/ml; range, 52--120,898) and CVL specimens (median, 265 copies/ml; range, 61--35,637;P = 0.88). CONCLUSION: Tampon eluent specimens are slightly less sensitive than CVL specimens in the detection of genital HIV-1, although quantification of viral load, when detectable by both methods, was similar.

Short tandem repeat methodology for genotypic identification of single-person versus multi-person use of syringes.

OBJECTIVE: To develop laboratory methods to differentiate between single- versus multi-person use of syringes by injection drug users. METHODS: Forensic short tandem repeat (STR) genetic analysis was undertaken to cross-validate a test panel of trace blood contents from syringes representing single- versus multi-person syringe use. Laboratory-simulated scenarios of needle sharing generated 34 syringe washes that were blinded for evaluation. Polymerase chain reaction was used to amplify the polymorphic STR locus D6S502 from blood trace contents in used syringes. Alleles were sized and quantified using a commercial gene sequencer. A statistical algorithm was developed to determine the number of alleles present in the amplified DNA fragments. Syringes with more than two expected alleles were considered to represent multi-person syringe use. Sensitivity, specificity and the kappa coefficient were calculated. RESULTS: Allelic matrix-based analysis of alleles from the single STR successfully characterized single-use (n = 12) and multiple-use (n = 22) syringes with 68% sensitivity and 100% specificity upon re-analysis. The extent of agreement over and above chance (kappa = 0.6; P < 0.0001) indicated good agreement for differentiating single- versus multi-person syringe use. CONCLUSIONS: These findings suggest that improved genotypic STR analysis of syringe material could be an adjunct to methods for validating self-reported needle sharing, conducting behavioral surveillance of needle-sharing behaviors, and evaluating interventions such as needle-exchange programs. Assays based on multiple STR loci will undoubtedly improve upon the promising results obtained from laboratory simulations of needle sharing.

Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection.

To understand the high variability of the asymptomatic interval between primary human immunodeficiency virus type 1 (HIV-1) infection and the development of AIDS, we studied the evolution of the C2-V5 region of the HIV-1 env gene and of T-cell subsets in nine men with a moderate or slow rate of disease progression. They were monitored from the time of seroconversion for a period of 6 to 12 years until the development of advanced disease in seven men. Based on the analysis of viral divergence from the founder strain, viral population diversity within sequential time points, and the outgrowth of viruses capable of utilizing the CXCR4 receptor (X4 viruses), the existence of three distinct phases within the asymptomatic interval is suggested: an early phase of variable duration during which linear increases ( approximately 1% per year) in both divergence and diversity were observed; an intermediate phase lasting an average of 1.8 years, characterized by a continued increase in divergence but with stabilization or decline in diversity; and a late phase characterized by a slowdown or stabilization of divergence and continued stability or decline in diversity. X4 variants emerged around the time of the early- to intermediate-phase transition and then achieved peak representation and began a decline around the transition between the intermediate and late phases. The late-phase transition was also associated with failure of T-cell homeostasis (defined by a downward inflection in CD3(+) T cells) and decline of CD4(+) T cells to

The effect of drug-injection behavior on genetic evolution of HIV-1.

The effect of injection-drug use on human immunodeficiency virus type 1 (HIV-1) env genetic evolution was examined in 15 seroconverting injection-drug users followed up for 4 years. After adjustment for non-drug-related independent variables significantly associated with genetic diversity (time since seroconversion and progressor status), injection frequency was positively and highly significantly associated with HIV-1 env genetic diversity (P=.003). The mutation rate in those who had injected at least once a day during the previous 6 months was estimated to be 62% greater than the rate in those who had not injected at all. If the positive effect of drug-injection frequency on env genetic diversity extends to the HIV-1 pol gene, the risk of emergence of resistance to antiretroviral drugs may be enhanced by increased drug-injection frequency, especially under the selection pressure of antiretroviral therapy.

Comparison of clinical manifestations of HIV infection among women by risk group, CD4+ cell count, and HIV-1 plasma viral load. HER Study Group. HIV Epidemiology Research.

OBJECTIVES: To compare the prevalence of HIV-related symptoms, physical examination findings, and hematologic variables among women whose risk for HIV is injection drug use since 1985 as opposed to sexual contact and to evaluate the influence of HIV plasma viral load and CD4+ cell count on clinical manifestations according to risk. METHODS: Participants of the HIV Epidemiology Research Study (HERS; a multicenter, prospective, controlled study of HIV infection in women) were administered a risk behavior and symptom interview, underwent a physical examination, and received hematologic testing, including CD4+ cell counts done on study entry. Plasma HIV-1 viral loads were performed on stored frozen plasma using an ultrasensitive branched-DNA (b-DNA) signal amplification assay. CD4+ counts were categorized as <200 cells/microl, 200 to 499 cells/microl, or > or =500 cells/microl, and HIV viral loads were characterized in tertiles. RESULTS: Cross-sectional analysis was conducted on data available for 724 HIV-infected women: 387 had a history of intravenous drug use and 337 were infected through heterosexual contact. The median CD4+ count was 376 cells/microl; the median HIV-1 viral load was 1135 copies/ml; and 281 of 724 HIV-infected women (38.8%) had an undetectable HIV-1 viral load. In analyses adjusting for CD4+ cell level alone and for plasma viral load combined with CD4+ cell level, injection drug users (IDUs) were more likely than those infected through heterosexual contact to report a recent episode of memory loss and weight loss, but less likely to have recent episodes of genital herpes; to have enlarged livers and a body mass index (BMI) <24, and to have hematocrit levels <34% and platelet counts <150,000 cells/ml. After adjustment for CD4+ cell level and risk group, high and medium HIV-1 plasma viral load levels were associated with the presence of oral hairy leukoplakia on examination, and only the highest level of plasma viral load was associated with recent histories of fever and thrush, oral hairy leukoplakia, pseudomembranous candidiasis, and BMI <24 on examination, and hematocrit <34%. CONCLUSIONS: In this cohort of women, the distribution of HIV-1 plasma viral load was lower than that previously reported in populations of HIV-infected men. This study also shows some differences in frequency of signs, symptoms, and laboratory values between risk groups of HIV-infected women, but these results may be due to effects of injection drug use rather than HIV infection. Signs and symptoms identified as associated with increasing levels of viral load that were not different across risk groups suggest more direct association of these findings with HIV infection.

Cell-associated infectious HIV-1 viral load as a predictor of clinical progression and survival among HIV-1 infected injection drug users and homosexual men.

Cell-associated infectious HIV-1 viral load was measured using semi-quantitative microculture techniques to determine its predictive capability for progression to AIDS or survival among HIV-1 infected injecting drug users (IDU) and homosexual men (HM). The authors followed 296 IDU and 240 HM from February 1992 through September 1995 for: (i) death, (ii) AIDS, and (iii) AIDS or bacterial infection. At baseline, viral load was quantified using microculture techniques to determine infectious units per million peripheral blood mononuclear cells (IUPM). Data were analyzed using standard statistical methods for survival analysis. Of the 536 total participants, 106 died (20%), and 98 of the 481 AIDS-free participants developed AIDS (20%). The relative hazard of AIDS for a viral load of > or = 100 IUPM, relative to a negative culture (0 IUPM), was 6.73 (95% CI: 2.23-20.3) after adjusting for risk group, initial CD4+ count, and other covariates. The adjusted relative hazard of death for a viral load of > or = 100 IUPM vs. 0 IUPM was 2.57 (95% CI: 0.97 6.80). Viral load predicted time to death within the < 200 cells/ul CD4+ stratum. The predictive value of viral load on HIV-1 progression did not vary by risk group. These data show that cell associated infectious HIV-1 viral load was significantly predictive of progression across risk groups for AIDS and death among those severely immune compromised.

Comparison of two measures of human immunodeficiency virus (HIV) type 1 load in HIV risk groups.

Levels of viral burden were compared across risk group and gender populations among 485 human immunodeficiency virus type 1 (HIV-1)-infected participants consisting of 190 male injection drug users (IDUs), 92 female IDUs, and 203 homosexual men. Viral burden was quantified by a microculture technique to determine cell-associated infectious units per 10(6) peripheral blood mononuclear cells (IUPM) and by reverse transcriptase PCR (Amplicor) to determine plasma HIV RNA levels. Adjusting for CD4(+) cell count, females had a lower infectious HIV load than all males combined (0. 33 log10 lower; P = 0.004), and homosexual men had a 0.29 log10 higher infectious viral load than all IDUs combined (P = 0.001). For HIV RNA levels, females had lower levels than males (0.19 log10 lower; P = 0.04), but no differences were observed by risk group. After controlling for percent CD4(+) cells, no differences were found by risk group for either assay, but females still had a 0.25 log10 lower infectious viral load than males (P = 0.04) and a viral RNA load similar to that of males (P = 0.25). The correlation between infectious viral load and HIV RNA load was 0.58 overall, which did not differ by gender or risk group. Our data suggest that differences in viral load may exist by gender and that any differences observed by risk group are driven predominantly by gender or percent CD4(+) cell differences. These data also confirm a moderate correlation between cell-associated infectious viral load and plasma HIV RNA load, which appears to be similar by gender and across risk groups.

Sex differences in HIV-1 viral load and progression to AIDS.

BACKGROUND: Plasma HIV-1 RNA measurements are used for initiation of antiretroviral treatments. Whether the viral-load association with prognosis is similar in women and men is unknown. METHODS: We studied 812 specimens from 650 injection-drug users (IDUs) participating in a continuous observational study of patients based in a community clinic. HIV-1 load was measured by branched-chain DNA on samples from 527 IDUs from the baseline visit, and by reverse-transcriptase PCR and quantitative microculture on samples from 285 IDUs at a follow-up visit 3 years later. FNDINGS: Women had lower median viral-load measurements than men by branched-chain DNA (3365 vs 8907 copies/mL; p=0.001), reverse-transcriptase PCR (45416 vs 93130 copies/mL; p=0.02), and quantitative microculture (5 vs 8 infectious units per million peripheral blood mononuclear cells; p=0.015). This association remained even after adjustment for CD4 cell count, race, and drug use within the previous 6 months. Time to AIDS was statistically similar for men and women in a univariate proportional-hazards model and in a model adjusting for CD4 cell count. Proportional-hazards models showed that women with the same viral load as men had a 1.6-fold higher risk of AIDS (95% CI 1.10-2.32); or, equivalently, that women with half the viral load of men had a similar time to AIDS as men. INTERPRETATION: Although a biological mechanism remains unclear, these data suggest that current recommendations for HIV-1 viral-load thresholds to initiate antiretroviral therapy should be revised downwards for women.

Anti-HIV type 1 memory cytotoxic T lymphocyte responses associated with changes in CD4+ T cell numbers in progression of HIV type 1 infection.

We investigated memory cytotoxic T lymphocyte (CTLm) responses to HIV-1 as a determinant of HIV-1 disease progression, in relation to plasma HIV-1 load and T lymphocyte numbers in a longitudinal study of 14 homosexual men with incident HIV-1 infection. Study participants were selected who exhibited failure of T cell homeostasis, i.e., a downward inflection in CD3+ T cells that occurs in >75% of persons 1.5 to 2.5 years before development of AIDS, and compared with participants who developed low CD4+ T cell counts associated with possible T cell homeostasis failure, a subject who progressed rapidly to AIDS without well-defined T cell inflection, and subjects who had long-term preservation of T cell homeostasis (nonprogressors). High CTLm responses against Gag, but not Pol or Env, soon after seroconversion were associated with a slower loss of CD4+ T cells 1-4 years after seroconversion. Anti-Env CTLm responses decreased in most subjects around the time that T cell homeostasis failed. Plasma HIV-1 RNA increased exponentially (1.59-fold per year) over the 5 years preceding failure of T cell homeostasis, and there was a shift from a non-syncytium-inducing/CCR5 coreceptor phenotype of HIV-1 to a syncytium-inducing/CXCR4 phenotype, regardless of high or increasing levels of anti-HIV-1 CTLm during this time. These observations suggest that decreases in CTLm and increasing virus load are independent factors contributing to HIV-1 disease progression.

Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline.

Evolution of HIV-1 env sequences was studied in 15 seroconverting injection drug users selected for differences in the extent of CD4 T cell decline. The rates of increase of either sequence diversity at a given visit or divergence from the first seropositive visit were both higher in progressors than in nonprogressors. Viral evolution in individuals with rapid or moderate disease progression showed selection favoring nonsynonymous mutations, while nonprogressors with low viral loads selected against the nonsynonymous mutations that might have resulted in viruses with higher levels of replication. For 10 of the 15 subjects no single variant predominated over time. Evolution away from a dominant variant was followed frequently at a later time point by return to dominance of strains closely related to that variant. The observed evolutionary pattern is consistent with either selection against only the predominant virus or independent evolution occurring in different environments within the host. Differences in the level to which CD4 T cells fall in a given time period reflect not only quantitative differences in accumulation of mutations, but differences in the types of mutations that provide the best adaptation to the host environment.

Infection with dual-tropic human immunodeficiency virus type 1 variants associated with rapid total T cell decline and disease progression in injection drug users.

The characteristics of sequential human immunodeficiency virus type 1 (HIV-1) isolates from 12 seroconverters among injection drug users selected for either rapid or slow disease progression were evaluated. All 6 patients who developed AIDS within 5 years were initially infected with syncytium-inducing (SI) variants or showed a transition from non-SI-inducing (NSI) to SI variants. Detection of SI variants was associated with rapid decline of both CD8+ and CD4+ T cells. In contrast, the 6 slow progressors carried only NSI variants and maintained stable or increasing CD8+ T cell levels. The SI variants that were associated with initial infection were dual tropic, with efficient replication in primary macrophages and T cell lines. These results suggest that the ability to replicate in macrophages, rather than the SI or NSI phenotype per se, may be an important determinant of HIV-1 transmission and that dual-tropic viruses, when transmitted, may be associated with rapid progression to AIDS.

Sustained cognitive decline in HIV infection: relationship to CD4+ cell count, plasma viremia and p24 antigenemia.

To determine the clinical and virological correlates of neuropsychological test performance decline in HIV infection, we measured viral burden in blood in 272 HIV-seropositive men without dementia in the Baltimore arm of the Multicenter AIDS Cohort Study (MACS). These measures were then related to neuropsychological (NP) decline, defined as a decline relative to prior best performance of 2.0 standard deviations or more on one or more neuropsychological tests. A short battery of NP tests (Mini-Screen Battery) was administered to all 272 men. NP test performance decline was identified in 53/272 (19.5%) of participants on the Mini-Screen Battery. Follow-up NP data were available for 204 participants who had undergone the Mini-Screen. The frequency of sustained NP test performance decline was 7.8% for the Mini-Screen Battery. A lower CD4+ cell count was weakly associated with sustained NP test performance decline. After adjustment for CD4+ cell count, hemoglobin, body mass index, and presence of AIDS, none of the viral burden measures (p24 antigenemia, plasma viremia, quantitative culture) correlated with sustained NP test performance decline. We conclude that these measures of blood HIV viral burden are not markers for NP decline, but that a lower CD4+ cell count is.

Vitamin A supplementation and human immunodeficiency virus load in injection drug users.

The use of vitamin A therapy during human immunodeficiency virus (HIV) infection is under clinical investigation, and vitamin A could potentially modulate HIV replication because the virus genome contains a retinoic acid response element. A randomized, double-masked, placebo-controlled clinical trial was conducted to determine the impact of single high-dose vitamin A supplementation, 60-mg retinol equivalent (200,000 IU), on HIV load and CD4 lymphocyte count. HIV-infected injection drug users (120) were randomly allocated to receive vitamin A or placebo. Plasma vitamin A level, CD4 lymphocyte count, and HIV load were measured at baseline and 2 and 4 weeks after treatment. Vitamin A supplementation had no significant impact on HIV load or CD4 lymphocyte count at 2 and 4 weeks after treatment. This study suggests that high-dose vitamin A supplementation does not influence HIV load.

Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count.

CONTEXT: Plasma human immunodeficiency virus type 1 (HIV-1) viral load and CD4+ cell count are used to predict prognosis of persons infected with HIV. However, whether combining these markers improves prognostic accuracy and whether they predict prognosis for injection drug users (IDUs) and nonwhite persons infected with HIV has not been extensively investigated. OBJECTIVE: To evaluate plasma viral load and CD4+ cell count as prognostic indicators for the acquired immunodeficiency syndrome (AIDS) and infectious disease deaths. DESIGN: Cohort study initiated in 1988 and 1989 with follow-up for up to 7.9 years. PARTICIPANTS: Injection drug users infected with HIV recruited from the community in Baltimore, Md. MAIN OUTCOME MEASURES: Plasma HIV-1 RNA and CD4+ cell count measured at baseline compared with time to first clinical AIDS diagnosis and death due to an infectious disease. RESULTS: Of 522 subjects, 96% were African American, 80% were male, 96% injected drugs within the past 6 months, and the median age was 33 years. A total of 146 cases of AIDS and 119 infectious disease deaths were seen during a median follow-up period of 6.4 years. Time-fixed baseline levels of viral load and CD4+ cell count were independent predictors of progression to AIDS and infectious disease deaths, but in proportional hazards models, viral load had better predictive value than CD4+ cell count. Kaplan-Meier analysis of time to AIDS and to infectious disease deaths by viral load (<500, 500-9999, 10000-29 999, > or =30000 copies/mL) at 3 levels of CD4+ cell count (<0.20, 0.20-0.49, and > or =0.50x10(9)/L [<200,200-499, and > or =500/microL]) was reduced to a 5-stage classification scheme using a backward stepwise regression procedure. The 5-year cumulative probabilities for AIDS and infectious disease deaths ranged from 0% and 0%, respectively, for group I (viral load, <500 copies/mL; CD4+ cell count, 0.50x10(9)/L) to 81.2% and 76.1% respectively, for group V (viral load, > or =10000 copies/mL; CD4+ cell count, 0.20x10(9)/L). CONCLUSIONS: In this study, plasma HIV-1 viral load independently and in combination with CD4+ cell count measurements provided powerful prognostic information for progression to AIDS and death caused by infectious disease in a population of predominantly African American IDUs. Combining categories of both markers provided a simple method for prognostically staging HIV disease.

Diagnosis of human immunodeficiency virus infection using citrated whole blood.

Standard isolation of human immunodeficiency virus type 1 (HIV-1) from peripheral blood mononuclear cells (PBMC) requires 5 to 20 ml of blood, and the centrifugal separation of PBMC is expensive and time-consuming. Whole-blood coculture techniques use small sample volumes, do not require centrifugation, and allow measurement of the total viral burden in peripheral circulation. We compared the results of citrated whole-blood coculture with those obtained by the standard AIDS Clinical Trials Group PBMC semiquantitative culture method and reverse transcription-PCR quantitation of plasma HIV-1 RNA levels. PBMC cocultures were also set up with added erythrocytes (RBCs) to determine if the presence of RBCs affects the replication of HIV-1 in vitro. The mean number of cells required for a p24-positive PBMC coculture was approximately seven times greater than that required for a positive citrated whole-blood coculture (P < 0.01). At volumes of 100, 50, and 25 microl, the sensitivities of the whole-blood coculture were 94.5, 93.6, and 87.3%, respectively. The PBMC culture in the presence of added RBCs was more sensitive than PBMC coculture alone. The citrated whole-blood coculture was simple to perform, produced a reliable diagnosis of HIV infection in adult volunteers, was more sensitive than previously reported techniques even in half the culture time, and showed less variability than the PBMC coculture. Citrated whole-blood coculture may be a useful and efficient tool for diagnosing infection with HIV-1.

Vitamin A levels and human immunodeficiency virus load in injection drug users.

Although low plasma vitamin A levels are associated with increased mortality and higher vertical transmission during human immunodeficiency virus (HIV) infection, it is unknown whether plasma low vitamin A levels are a marker for circulating HIV load. We conducted a cross-sectional study within a prospective cohort study of injection drug users in order to evaluate the relationship between plasma vitamin A levels and HIV viral load. Plasma vitamin A level was measured by high-performance liquid chromatography. Infectious viral load was measured by quantitative microculture of serial fivefold dilutions of 10(6) peripheral blood mononuclear cells. A total of 284 HIV-infected adults (79 women, 205 men) were studied. Plasma vitamin A levels consistent with deficiency were found in 28.9% of adults. A total of 38.0% of women and 25.3% of men had vitamin A deficiency (P < 0.04). The median infectious viral load for the entire study population was 8 infectious units per million cells. No significant relationship between plasma vitamin A levels and infectious viral load was observed in these injection drug users. This study suggests that there is no correlation between HIV viral load and plasma vitamin A levels in injection drug users, and these variables may represent independent risk factors during HIV infection. HIV-infected adult women appear to be at higher risk of developing vitamin A deficiency.

Virologic and serologic markers of rapid progression to AIDS after HIV-1 seroconversion.

The association between early virologic and immunologic events after human immunodeficiency virus type 1 (HIV-1) infection and progression of HIV-1 infection to acquired immunodeficiency syndrome (AIDS) was studied among 59 homosexual men with documented time of seroconversion. Epidemiologic factors, such as number of lifetime sexual partners, history of sexually transmitted diseases, and other factors, also were studied. All 17 seroconverters in the cohort who developed AIDS within 3 years (rapid progressors = RPs) were compared with 42 men without AIDS for at least 6 years seroconversion (nonrapid progressors = non-RPs). Plasma levels of HIV-1 RNA, p24 antigen, antibodies to HIV-1 structural genes, beta-2 microglobulin, neopterin, and interferon-alpha were measured at four time points: (a) the last seronegative visit, (b) the first seropositive visit, (c) the visit closest to AIDS (or the corresponding visit for the non-RPs) and (d) 6 years after seroconversion (for non-RPs). Up to seroconversion, the RPs had a significantly higher number of lifetime sexual partners than non-RPs (503 versus 171, respectively). At the first seropositive visit, RPs had significantly higher concentrations of plasma HIV-1 RNA (p < 0.01) and prevalence of p24 antigenemia (p < 0.001) and significantly lower levels of antibodies to the HIV-1 gag proteins p17 and p24 (p < 0.01-0.001) compared with non-RPs. These differences increased during follow-up visits. Antibodies to p66 and gp120 were significantly different only at the visit closet to AIDS (p < 0.001), as were beta-2 microglobulin and interferon alpha. These findings suggest that early virologic-immunologic events after HIV-1 infection may determine the rate of progression to AIDS. Anti-gag immune response may prevent rapid progression of HIV-1 disease and should be considered for future vaccine studies.

The effect of influenza vaccination on human immunodeficiency virus type 1 load: a randomized, double-blind, placebo-controlled study.

To determine if vaccination induces replication of human immunodeficiency virus type 1 (HIV-1), 42 HIV-1-infected subjects with CD4 cell counts of 200-500 cells/microL were randomized to receive influenza vaccine or saline placebo. Infectious cell-associated and plasma HIV-1 RNA virus load were measured twice at baseline and then at 7, 10, 14, and 30 days after injection by quantitative microculture and branched DNA amplification. The ratios of the geometric mean plasma HIV-1 load of the four follow-up visits compared with baseline in vaccine (n = 28) and placebo (n = 14) recipients were similar (1.05 [95% confidence interval, 0.80-1.37] for vaccine; 0.96 [95% confidence interval, 0.68-1.33] for placebo; P = .90). The geometric mean ratios of plasma virus load at each follow-up visit to baseline did not differ significantly from 1.0 for each group. Infectious cell-associated virus load measures yielded similar results. CD4 cell counts declined similarly in both groups at 6 months. Influenza vaccination did not increase HIV-1 load in this controlled clinical trial.