Safety and immunogenicity study of Multiclade HIV-1 adenoviral vector vaccine alone or as boost following a multiclade HIV-1 DNA vaccine in Africa.

BACKGROUND: We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults. METHODOLOGY/PRINCIPAL FINDINGS: Volunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1×10(10) or 1×10(11) particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector® 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-γ) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-γ ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone. CONCLUSIONS/SIGNIFICANCE: The HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints. TRIAL REGISTRATION: ClinicalTrials.gov NCT00124007.

Characterization of an HLA-C-restricted CTL response in chronic HIV infection.

HIV-specific CTL play an important role in the host control of HIV infection. HIV-nef may facilitate escape of HIV-infected cells from CTL recognition by selectively downregulating the expression of HLA-A and HLA-B molecules, while surface expression of HLA-C is unaffected. The HLA-C-restricted CTL responses have previously been largely ignored and poorly characterized. We examined the frequency, function, and phenotype of HLA-C-restricted CTL in ten antiretroviral therapy-naïve Caucasian and African individuals with chronic HIV-1 infection (for at least 8 years; CD4 cell counts in the range of 50-350) who carried the HLA-Cw04 allele. HLA-Cw04-restricted CTL that recognize a conserved epitope within HIV-1 envelope (aa 375-383 SF9) were analyzed using IFN-gamma ELISPOT assays and phenotypic analysis was carried out by flow cytometry. HLA-C-restricted CTL play an important role in the HIV-specific response, and can account for as much as 54% of the total response. HLA-C-restricted CTL are functionally and phenotypically identical to HLA-A- and HLA-B-restricted CTL. HLA-C-restricted CTL in chronic HIV infection are memory cells of an intermediate phenotype, characterized by high CD27 and low CD28 expression and lack of perforin production.

Mucosal Neisseria gonorrhoeae coinfection during HIV acquisition is associated with enhanced systemic HIV-specific CD8 T-cell responses.

BACKGROUND: The host immune response against mucosally acquired pathogens may be influenced by the mucosal immune milieu during acquisition. As Neisseria gonorrhoeae can impair dendritic cell and T-cell immune function, we hypothesized that coinfection during HIV acquisition would impair subsequent systemic T-cell responses. METHODS: Monthly screening for sexually transmitted infections was performed in high risk, HIV seronegative Kenyan female sex workers as part of an HIV prevention trial. Early HIV-specific CD8 T-cell responses and subsequent HIV viral load set point were assayed in participants acquiring HIV, and were correlated with the presence of prior genital infections during HIV acquisition. RESULTS: Thirty-five participants acquired HIV during follow-up, and 16 out of 35 (46%) had a classical sexually transmitted infection at the time of acquisition. N. gonorrhoeae coinfection was present during HIV acquisition in 6 out of 35 (17%), and was associated with an increased breadth and magnitude of systemic HIV-specific CD8 T-cell responses, using both interferon-gamma gamma and MIP-1 beta as an output. No other genital infections were associated with differences in HIV-specific CD8 T-cell response, and neither N. gonorrhoeae nor other genital infections were associated with differences in HIV plasma viral load at set point. CONCLUSION: Unexpectedly, genital N. gonorrhoeae infection during heterosexual HIV acquisition was associated with substantially enhanced HIV-specific CD8 T-cell responses, although not with differences in HIV viral load set point. This may have implications for the development of mucosal HIV vaccines and adjuvants.

An evaluation of intravaginal rings as a potential HIV prevention device in urban Kenya: behaviors and attitudes that might influence uptake within a high-risk population.

PURPOSE: We sought to assess the potential acceptability of intravaginal rings (IVRs) as an HIV prevention method among at-risk women and men. METHODS: We conducted a qualitative assessment of initial attitudes toward IVRs, current HIV prevention methods, and common behavioral practices among female sex workers (FSWs) and men who frequent FSWs in Mukuru, an urban slum community in Nairobi, Kenya. Nineteen women and 21 men took part in six focus group discussions. RESULTS: Most participants, both male and female, responded positively to the concept of an IVR as a device for delivering microbicides. Women particularly liked the convenience offered by its slow-release capacity. Some female respondents raised concerns about whether male customers would discover the ring and respond negatively, whereas others thought it unlikely that their clients would feel the ring. Focus groups conducted with male clients of FSWs suggested that many would be enthusiastic about women, and particularly sex workers, using a microbicide ring, but that women's fears about negative responses to covert use were well founded. Overall, this high-risk population of FSWs and male clients in Nairobi was very open to the IVR as a potential HIV prevention device. CONCLUSION: Themes that emerged from the focus groups highlight the importance of understanding attitudes toward IVRs as well as cultural practices that may impact IVR use in high-risk populations when pursuing clinical development of this potential HIV prevention device.

Coinfection with herpes simplex virus type 2 is associated with reduced HIV-specific T cell responses and systemic immune activation.

BACKGROUND: Chronic coinfection with herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) has been associated with an increased HIV viral load and more rapid disease progression, perhaps related to HSV-2-associated alterations in host immunity. METHODS: Studies were nested within (1) a cross-sectional study of men coinfected with HIV and HSV-2 and (2) women not infected with HIV, both before and after HSV-2 acquisition. HSV-2 infection status was determined by ELISA. HIV-specific CD8(+) T cell epitopes were mapped, and proliferation of HIV-specific cells was also assessed. Systemic inflammatory and regulatory T cell populations were assayed by flow cytometry. RESULTS: The breadth of both the HIV-specific CD8(+) T cell interferon-gamma and proliferative responses was reduced in participants coinfected with HIV and HSV-2, independent of the HIV plasma viral load and CD4(+) T cell count, and the magnitude of the responses was also reduced. HSV-2 infection in this group was associated with increased T cell CD38 expression but not with differences in the proportion of CD4(+) FoxP3(+) regulatory T cells. However, in women not infected with HIV, acquisition of HSV-2 was associated with an increase in the proportion of regulatory T cells. CONCLUSIONS: HSV-2 coinfection was associated with reduced HIV-specific T cell responses and systemic inflammation. The immune effects of HSV-2 may underlie the negative impact that this coinfection has on the clinical course of HIV infection.

Safety and immunogenicity of recombinant low-dosage HIV-1 A vaccine candidates vectored by plasmid pTHr DNA or modified vaccinia virus Ankara (MVA) in humans in East Africa.

The safety and immunogenicity of plasmid pTHr DNA, modified vaccinia virus Ankara (MVA) human immunodeficiency virus type 1 (HIV-1) vaccine candidates were evaluated in four Phase I clinical trials in Kenya and Uganda. Both vaccines, expressing HIV-1 subtype A gag p24/p17 and a string of CD8 T-cell epitopes (HIVA), were generally safe and well-tolerated. At the dosage levels and intervals tested, the percentage of vaccine recipients with HIV-1-specific cell-mediated immune responses, assessed by a validated ex vivo interferon gamma (IFN-gamma) ELISPOT assay and Cytokine Flow Cytometry (CFC), did not significantly differ from placebo recipients. These trials demonstrated the feasibility of conducting high-quality Phase 1 trials in Africa.

HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers.

OBJECTIVES: HIV-neutralizing immunoglobulin A (IgA) and HIV-specific cellular immunity have been described in highly exposed, persistently seronegative (HEPS) individuals, but well controlled studies have not been performed. We performed a prospective, nested case-control study to examine the association of genital IgA and systemic cellular immune responses with subsequent HIV acquisition in high-risk Kenyan female sex workers (FSWs). DESIGN AND METHODS: A randomized trial of monthly antibiotic prophylaxis to prevent sexually transmitted disease/HIV infection was performed from 1998 to 2002 in HIV-uninfected Kenyan FSWs. After the completion of trial, FSWs who had acquired HIV (cases) were matched 1: 4 with persistently uninfected controls based on study arm, duration of HIV-seronegative follow-up, and time of cohort enrolment. Blinded investigators assayed the ability at enrolment of genital IgA to neutralize primary HIV isolates as well as systemic HIV-specific cellular IFNgamma-modified enzyme-linked immunospot and proliferative responses. RESULTS: The study cohort comprised 113 FSWs: 24 cases who acquired HIV and 89 matched controls. Genital HIV-neutralizing IgA was associated with reduced HIV acquisition (P = 0.003), as was HIV-specific proliferation (P = 0.002), and these associations were additive. HIV-specific IFNgamma production did not differ between case and control groups. In multivariable analysis, HIV-neutralizing IgA and HIV-specific proliferation each remained independently associated with lack of HIV acquisition. Genital herpes (HSV2) was associated with increased HIV risk and with reduced detection of HIV-neutralizing IgA. CONCLUSION: Genital HIV-neutralizing IgA and systemic HIV-specific proliferative responses, assayed by blinded investigators, were prospectively associated with HIV nonacquisition. The induction of these immune responses may be an important goal for HIV vaccines.

HIV-1 neutralizing activity is correlated with increased levels of chemokines in saliva of HIV-1-exposed uninfected individuals.

AIM: Mucosal HIV-1 exposure stimulates a variety of mucosal immune responses, including IgA1-mediated virus neutralization, even in the absence of an established infection. We hypothesized that other immune molecules might also contribute to the HIV-1 neutralizing activity observed in the mucosal secretions of HIV-1 exposed uninfected individuals. METHODS: Saliva samples were collected from HIV-1 seronegative high-risk female sex workers (FSW) from Nairobi. Samples were also collected from HIV-1 IgG positive FSW and HIV-1 IgG negative low-risk women from the same geographical area. In all samples, IgA2, secretory leukocyte protease inhibitor (SLPI), regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha and beta (MIP-1alpha and -beta) and monocyte chemoattractant protein-1 (MCP-1) were quantified. The IgA1-depleted saliva samples were subsequently tested for neutralizing capacity in a PBMC-based neutralization assay using a primary HIV-1 clade A isolate to determine biological relevance of the measured molecules. RESULTS: HIV-1 specific neutralization was present in the IgA1-depleted fraction from saliva of both HIV-1 seropositive (9 of 10) and high-risk individuals (36 of 45) but not in HIV-1 IgG-negative control subjects (0 of 8). In the high-risk individuals, higher levels of CC-chemokines were seen in those that could neutralize HIV-1 as compared with those that could not (P<0.05). CONCLUSION: The HIV-1 neutralizing activity in saliva of HIV-1-exposed high-risk individuals is not only mediated by IgA1, but is also present in IgA1-depleted fractions and is associated with increased levels of CC-chemokines. Such innate immune factors may be important in limiting HIV-1 mucosal transmission.

Prevalent herpes simplex virus type 2 infection is associated with altered vaginal flora and an increased susceptibility to multiple sexually transmitted infections.

BACKGROUND: Prevalent herpes simplex virus type 2 (HSV-2) infection increases human immunodeficiency virus acquisition. We hypothesized that HSV-2 infection might also predispose individuals to acquire other common sexually transmitted infections (STIs). METHODS: We studied the association between prevalent HSV-2 infection and STI incidence in a prospective, randomized trial of periodic STI therapy among Kenyan female sex workers. Participants were screened monthly for infection with Neisseria gonorrhoeae and Chlamydia trachomatis, and at least every 6 months for bacterial vaginosis (BV) and infection with Treponema pallidum, Trichomonas vaginalis, and/or HSV-2. RESULTS: Increased prevalence of HSV-2 infection and increased prevalence of BV were each associated with the other; the direction of causality could not be determined. After stratifying for sexual risk-taking, BV status, and antibiotic use, prevalent HSV-2 infection remained associated with an increased incidence of infection with N. gonorrhoeae (incidence rate ratio [IRR], 4.3 [95% confidence interval {CI}, 1.5-12.2]), T. vaginalis (IRR, 2.3 [95% CI, 1.3-4.2]), and syphilis (IRR, 4.7 [95% CI, 1.1-19.9]). BV was associated with increased rates of infection with C. trachomatis (IRR, 2.1 [95% CI, 1.1-3.8]) and T. vaginalis (IRR, 8.0 [95% CI, 3.2-19.8]). CONCLUSION; Increased prevalences of HSV-2 infection and BV were associated with each other and also associated with enhanced susceptibility to an overlapping spectrum of other STIs. Demonstration of causality will require clinical trials that suppress HSV-2 infection, BV, or both.

Sustained changes in sexual behavior by female sex workers after completion of a randomized HIV prevention trial.

INTRODUCTION: Behavioral interventions in female sex workers (FSWs) are associated with changes in sexual behavior and reduced rates of sexually transmitted infections (STIs) and HIV We examined the sustainability of such interventions. METHODS: HIV-uninfected Kenyan FSWs were enrolled in a clinical trial that provided free male condoms, community and clinic-based counseling, and STI management. After trial completion, scaled-back community-based resources remained in place. More than a year later, women were invited to complete a follow-up behavioral questionnaire and to undergo STI/HIV counseling and testing. Individual changes in sexual behavior were assessed by paired analysis. RESULTS: One hundred seventy-two women participated in the resurvey 1.2 years after trial termination. Client numbers had risen (paired t test, P < 0.001), but condom use had also increased (P < 0.001); both remained substantially lower than at enrollment. Regular partners accounted for a greater proportion of unprotected FSW sexual encounters (35% vs. 10%; P < 0.001). Only 9 (5.2%) of 172 women had a conventional STI, and the follow-up HIV incidence of 1.6 per 100 person-years (PYs) was similar to that during the trial period (3.7 per 100 PYs). Incident STIs and HIV were associated with the frequency of unprotected sex and younger age. CONCLUSIONS: Less intensive community-based risk reduction services after clinical trial termination may support ongoing reductions in STIs and HIV among high-risk FSWs.

Relationship between markers of HIV-1 disease progression and serum beta-carotene concentrations in Kenyan women.

Observational studies have suggested that low serum beta-carotene concentrations may influence HIV-1 disease progression. However, randomized trials have not demonstrated beneficial effects of beta-carotene supplementation. To understand this discrepancy, we conducted a cross-sectional study among 400 HIV-1-seropositive women in Mombasa, Kenya, to correlate serum beta-carotene concentrations with several measures of HIV-1 disease severity. beta-Carotene concentrations were significantly associated with biologic markers of HIV-1 disease progression (CD4 count, HIV-1 plasma viral load, serum C-reactive protein [CRP] concentration, and serum albumin level). In multivariate analysis, beta-carotene concentrations below the median were associated with elevated CRP (>10 mg/l, adjusted odds ratio [aOR] 3.32, 95% confidence interval [CI] 1.99-5.53, P<0.001) and higher HIV-1 plasma viral load (for each log(10) copies/mL increase, aOR 1.38, 95% CI 1.01-1.88, P=0.04). In the context of negative findings from randomized trials of beta-carotene supplementation in HIV-1-seropositive individuals, these results suggest that low beta-carotene concentrations primarily reflect more active HIV-1 infection rather than a deficiency amenable to intervention.

Studies of a prophylactic HIV-1 vaccine candidate based on modified vaccinia virus Ankara (MVA) with and without DNA priming: effects of dosage and route on safety and immunogenicity.

BACKGROUND: Two parallel studies evaluated safety and immunogenicity of a prophylactic HIV-1 vaccine in 192 HIV-seronegative, low-risk volunteers. Modified vaccinia virus Ankara (MVA) and plasmid DNA (pTHr) expressed HIV-1 clade A gag p24 and p17 fused to a string of 25 overlapping CD8+ T cell epitopes (HIVA). METHODS: These studies compared intramuscular, subcutaneous, and intradermal MVA at dosage levels ranging from 5x10(6)-2.5x10(8) pfu. In Study IAVI-010, DNA vaccine was given as a prime at months 0 and 1, followed by MVA as a boost at months 5 and 8. In Study IAVI-011, MVA alone was given at months 0 and 2. Regular safety monitoring was performed. Immunogenicity was measured by the interferon (IFN)-gamma ELISPOT assay on peripheral blood mononuclear cells (PBMC). RESULTS: No serious adverse events were attributed to either vaccine; most adverse events were mild or moderate, although MVA resulted in some severe local reactions. Five vaccine recipients had at least one positive IFN-gamma ELISPOT response, but none were sustained. CONCLUSION: This HIV-1 vaccine candidate was in general safe and well-tolerated. Local reactions were common, but tolerable. Detectable immune responses were infrequent.

Strong TCR conservation and altered T cell cross-reactivity characterize a B*57-restricted immune response in HIV-1 infection.

HLA-B*57 is associated with slower disease progression to AIDS, and CD8+ T cell responses to B*57-restricted epitopes are thought to contribute to this protective effect. In this study, we evaluate the B*57-restricted p24 KAFSPEVIPMF (KF11) immune response which is immunodominant during chronic infection. Previously, we observed that the KF11 clade variants KGFNPEVIPMF [A2G,S4N] and KAFNPEIIMPF [S4N,V7I], sharing a position 4 mutation, are differentially recognized by KF11-specific T cells. By combining structural and cellular studies, we now demonstrate that the KF11 and [A2G,S4N] epitopes induce distinct functional responses in [A2G,S4N] and KF11-specific T cells, respectively, despite minimal structural differences between the individual B*57-peptide complexes. Recently, we also elucidated the highly distinct structure of KF11 in complex with B*5703, and have now characterized the CD8+ T cell repertoire recognizing this epitope. We now report striking features of TCR conservation both in terms of TCR Valpha and Vbeta chain usage, and throughout the hypervariable region. Collectively, our findings highlight unusual features of the B*5701/B*5703-KF11-specific immune responses which could influence disease progression and that might be important to consider when designing future vaccine regimens.

HIV-1 infection alters the retinol-binding protein:transthyretin ratio even in the absence of the acute phase response.

The ratio of retinol-binding protein (RBP) to transthyretin (TTR) has been proposed as an indirect method with which to assess vitamin A status in the context of inflammation. Few studies have been conducted among adults, and none examined the effect of HIV-1 infection. Our goal was to assess the RBP:TTR ratio among adults, including the effects of HIV-1 and the acute phase response. We used data from a cross-sectional study of 600 Kenyan women, of whom 400 had HIV-1. The effect of vitamin A supplementation among the HIV-1-infected participants was subsequently assessed in a randomized trial. Among HIV-1-uninfected women without an acute phase response, a RBP:TTR cut-off value of 0.25 had approximately 80% sensitivity and specificity to detect vitamin A deficiency (retinol <0.70 micromol/L). No RBP:TTR cut-off value demonstrated both high sensitivity and specificity among HIV-1 infected women without evidence of inflammation. HIV-1 infection and advanced HIV-1 disease were associated with higher RBP:TTR ratios. The effect of HIV-1 was independent of the acute phase response, which also increased the RBP:TTR ratio. Serum retinol increased with vitamin A supplementation among those with a low RBP:TTR ratio, although the effect was small and was not present among those with concurrent inflammation. Thus, the RBP:TTR ratio has modest ability to predict vitamin A deficiency among healthy adults, but HIV-1 infection alters the ratio, even in the absence of the acute phase response. Our results raise questions about the utility of this measurement given the high prevalence of HIV-1 infection in areas where vitamin A deficiency is common.

Identification of a novel HLA B*57 restricted cytotoxic T-lymphocyte epitope within HIV-1 rev.

HLA-B5701 and its related allele B5703 have been shown to be strongly associated with slow HIV-1 disease progression. To elucidate the effect of these alleles fully on disease progression it is essential to identify key HIV-1 epitopes that are restricted by these alleles. Here we describe the identification of a novel HLA-B5701, B5703 restricted epitope within HIV-1 rev, which accounted for up to 25 and 40% of the total cytotoxic T-lymphocyte responses in two patients.

HIV impact on acute morbidity and pelvic tumor control following radiotherapy for cervical cancer.

OBJECTIVE: To determine the impact of HIV infection on acute morbidity and pelvic tumor control following external beam radiotherapy (EBRT) for cervical cancer. METHOD: 218 patients receiving EBRT who also had HIV testing after informed consent was obtained were evaluated. Acute treatment toxicity was documented weekly during treatment and 1 month post-EBRT. Pelvic tumor control was documented at 4 and 7 months post-EBRT. Clinicians were blinded for HIV results. RESULTS: About 20% of the patients were HIV-positive. Overall, 53.4% of the patients had radiation-related acute toxicity (grade 3-4). HIV infection was associated with a 7-fold higher risk of multisystem toxicity: skin, gastrointestinal tract (GIT) and genitourinary tract (GUT) systems. It was also an independent risk factor for treatment interruptions (adjusted relative risk 2.2). About 19% of the patients had residual tumor at 4 and 7 months post-EBRT. HIV infection was independently and significantly associated with 6-fold higher risk of residual tumor post-EBRT. The hazard ratio of having residual tumor after initial EBRT was 3.1-times larger for HIV-positive than for HIV-negative patients (P = 0.014). CONCLUSION: HIV is associated with increased risk of multisystem radiation-related toxicity; treatment interruptions and pelvic failure (residual tumor) following EBRT. HIV infection is an adverse prognostic factor for outcome of cervical cancer treatment.

Associations of sexual risk taking among Kenyan female sex workers after enrollment in an HIV-1 prevention trial.

BACKGROUND: Female sex workers (FSWs) often lack the ability to negotiate safer sex and are at high risk for HIV-1 infection and sexually transmitted infections (STIs). METHODS: Seronegative FSWs were enrolled in an STI/HIV-1 prevention trial in Nairobi, Kenya. Demographics and sexual risk taking were assessed every 3 months. Predictors of reduced risk taking were defined using multivariate logistic regression. RESULTS: Four hundred sixty-six FSWs were enrolled and followed for just over 2 years each. A spectrum of sex work was apparent: FSWs working in night clubs were younger, charged more for sex, and used condoms more frequently; FSWs working from home were older, charged less, and used condoms the least; and those working in bars were intermediate. Increases in reported condom use were most significant and sustained for FSWs working from home and charging less for sex and were poorly maintained for bar-based FSWs. Self-reported lower condom use, higher client numbers, and alcohol use were associated with higher STI rates. CONCLUSIONS: Home-based FSWs and those charging less for sex used condoms the least at baseline but showed the greatest and most sustained improvements over time. Potential response heterogeneity in FSW subgroups should be considered in the design of HIV-1 prevention programs.

Female-to-male infectivity of HIV-1 among circumcised and uncircumcised Kenyan men.

BACKGROUND: A lack of male circumcision has been associated with increased risk of human immunodeficiency virus type 1 (HIV-1) acquisition in a number of studies, but questions remain as to whether confounding by behavioral practices explains these results. The objective of the present study was to model per-sex act probabilities of female-to-male HIV-1 transmission (i.e., infectivity) for circumcised and uncircumcised men, by use of detailed accounts of sexual behavior in a population with multiple partnerships. METHODS: Data were collected as part of a prospective cohort study of HIV-1 acquisition among 745 Kenyan truck drivers. Sexual behavior with wives, casual partners, and prostitutes was recorded at quarterly follow-up visits. Published HIV-1 seroprevalence estimates among Kenyan women were used to model HIV-1 per-sex act transmission probabilities. RESULTS: The overall probability of HIV-1 acquisition per sex act was 0.0063 (95% confidence interval, 0.0035-0.0091). Female-to-male infectivity was significantly higher for uncircumcised men than for circumcised men (0.0128 vs. 0.0051; P=.04). The effect of circumcision was robust in subgroup analyses and across a wide range of HIV-1 prevalence estimates for sex partners. CONCLUSIONS: After accounting for sexual behavior, we found that uncircumcised men were at a >2-fold increased risk of acquiring HIV-1 per sex act, compared with circumcised men. Moreover, female-to-male infectivity of HIV-1 in the context of multiple partnerships may be considerably higher than that estimated from studies of HIV-1-serodiscordant couples. These results may explain the rapid spread of the HIV-1 epidemic in settings, found throughout much of Africa, in which multiple partnerships and a lack of male circumcision are common.

Micronutrient supplementation increases genital tract shedding of HIV-1 in women: results of a randomized trial.

To test the hypothesis that micronutrient supplementation decreases genital HIV-1 shedding, a double-blind, randomized, placebo-controlled trial of 6 weeks of multivitamin plus selenium supplementation vs. placebo was conducted among 400 HIV-1-seropositive, nonpregnant, antiretroviral-naive women in Mombasa, Kenya. Primary outcome measures included cervical and vaginal shedding of HIV-1-infected cells and RNA. Secondary outcomes included plasma viral load and CD4 count. Surprisingly, the odds of detection of vaginal HIV-1-infected cells were 2.5-fold higher (P = 0.001) and the quantity of HIV-1 RNA in vaginal secretions was 0.37 log10 copies/swab higher (P = 0.004) among women who received micronutrients in comparison to placebo, even after adjustment for potential confounders including baseline HIV-1 shedding and CD4 count. The increase in vaginal HIV-1 shedding was greatest among women who had normal baseline selenium levels. Micronutrient supplementation resulted in higher CD4 (+23 cells/microL, P = 0.03) and CD8 (+74 cells/microL, P = 0.005) counts compared with placebo but did not alter the plasma viral load. In this randomized trial, micronutrients resulted in higher levels of genital HIV-1 shedding compared with placebo. The potential benefit of micronutrient supplementation in HIV-1-seropositive women should be considered in relation to the potential for increased infectivity.

HIV-1 Env-specific cytotoxic T-lymphocyte responses in exposed, uninfected Kenyan sex workers: a prospective analysis.

The prospective significance of HIV-specific cytotoxic T lymphocyte (CTL) responses in highly exposed, persistently seronegative populations is unknown. In 1996-1997 we screened for CTL responses against HIV clade B Env in 39 recently enrolled Kenyan female sex workers, and followed these women prospectively. Annual HIV incidence was 5.8%. CTL were independently associated with age and recent HIV-1 exposure,but were not prospectively associated with protection in a multivariable model that included HIV-1 exposure and duration of sex work.