KNH-UoN Ethics and Research Committee

 We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.

Evidence suggests that specific vaginal bacteria associated with bacterial vaginosis (BV) may increase the risk of adverse health outcomes in women. Among women participating in a randomized, double-blinded trial, we assessed the effect of periodic presumptive treatment (PPT) on detection of select vaginal bacteria.

Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women.

The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ∼11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.

Sexually transmitted infections (STIs) are a major public health problem, especially in developing countries. The complications of untreated STIs in the female genital tract and their role in adverse pregnancy and perinatal outcomes have been well documented. The prevalence of STIs in Kenya among women in the general population has not been extensively studied and there is a lack of guidelines for screening of non-pregnant women. Knowledge of the prevalence of curable STIs among this population can provide a basis for integrating STI screening in family planning clinics.

Bacterial vaginosis (BV) may increase women's susceptibility to sexually transmitted infections (STIs). In a randomized trial of periodic presumptive treatment (PPT) to reduce vaginal infections, we observed a significant reduction in BV. We further assessed the intervention effect on incident Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium infection.

A prophylactic HIV-1 vaccine is a global health priority.

Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.

Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study.

In individuals with human immunodeficiency virus type 1 (HIV-1) infection, CD4:CD8 lymphocyte ratio is often recognized as a quantitative outcome that reflects the critical role of both CD4(+) and CD8(+) T-cells in HIV-1 pathogenesis or disease progression. Our work aimed to first establish the dynamics and clinical relevance of CD4:CD8 ratio in a cohort of native Africans and then to examine its association with viral and host factors, including: (i) length of infection, (ii) demographics, (iii) HIV-1 viral load (VL), (iv) change in CD4(+) T-lymphocyte count (CD4 slope), (v) HIV-1 subtype, and (vi) host genetics, especially human leukocyte antigen (HLA) variants. Data from 499 HIV-1 seroconverters with frequent (monthly to quarterly) follow-up revealed that CD4:CD8 ratio was stable in the first 3 years of infection, with a modest correlation with VL and CD4 slope. A relatively normal CD4:CD8 ratio (>1.0) in early infection was associated with a substantial delay in disease progression to severe immunodeficiency (<350 CD4 cells/μl), regardless of other correlates of HIV-1 pathogenesis (adjusted hazards ratio (HR) = 0.43, 95% confidence interval (CI) = 0.29-0.63, P < 0.0001). Low VL (<10,000 copies/ml) and HLA-A*74:01 were the main predictors of CD4:CD8 ratio >1.0, but HLA variants (e.g., HLA-B*57 and HLA-B*81) previously associated with VL and/or CD4 trajectories in eastern and southern Africans had no obvious impact on CD4:CD8 ratio. Collectively, these findings suggest that CD4:CD8 ratio is a robust measure of immunologic health with both clinical and epidemiological implications.

Serum was analyzed from 146 healthy adult volunteers in eastern Africa to evaluate measles virus (MV) and canine distemper virus (CDV) neutralizing antibody (nAb) prevalence and potency. MV plaque reduction neutralization test (PRNT) results indicated that all sera were positive for MV nAbs. Furthermore, the 50% neutralizing dose (ND50) for the majority of sera corresponded to antibody titers induced by MV vaccination. CDV nAbs titers were low and generally were detected in sera with high MV nAb titers. A mutant CDV was generated that was less sensitive to neutralization by human serum. The mutant virus genome had 10 nucleotide substitutions, which coded for single amino acid substitutions in the fusion (F) and hemagglutinin (H) glycoproteins and two substitutions in the large polymerase (L) protein. The H substitution occurred in a conserved region involved in receptor interactions among morbilliviruses, implying that this region is a target for cross-reactive neutralizing antibodies.

HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.

Vaginal infections are common, frequently recur, and may increase women's risk for sexually transmitted infections (STIs). We tested the efficacy of a novel regimen to prevent recurrent vaginal infections.

A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a "relaxed" definition (accounting for off-prescription dosing) and 40 % per a "strict" definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.

The hallmark of HIV infection is progressive but variable rates of systemic and mucosal CD4 depletion, leading to immunodeficiency. The impact of early HIV infection on cervical CD4 T-cell populations in humans remains poorly described.

Mucosal specimens are essential to evaluate compartmentalized immune responses to HIV vaccine candidates and other mucosally targeted investigational products. We studied the acceptability and feasibility of repeated mucosal sampling in East African clinical trial participants at low risk of HIV and other sexually transmitted infections.

Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of "missing heritability" in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.

In HIV-1 infection, plasma viral load (VL) has dual implications for pathogenesis and public health. Based on well-known patterns of HIV-1 evolution and immune escape, we hypothesized that VL is an evolving quantitative trait that depends heavily on duration of infection (DOI), demographic features, human leukocyte antigen (HLA) genotypes and viral characteristics. Prospective data from 421 African seroconverters with at least four eligible visits did show relatively steady VL beyond 3 months of untreated infection, but host and viral factors independently associated with cross-sectional and longitudinal VL often varied by analytical approaches and sliding time windows. Specifically, the effects of age, HLA-B(⁎)53 and infecting HIV-1 subtypes (A1, C and others) on VL were either sporadic or highly sensitive to time windows. These observations were strengthened by the addition of 111 seroconverters with 2-3 eligible VL results, suggesting that DOI should be a critical parameter in epidemiological and clinical studies.

Emergence of SIV and HIV specific CD8 T cells has been shown to correlate with control of in vivo replication. Poor correlation between IFN-γ ELISPOT responses and in vivo control of the virus has triggered the development of more relevant assays to assess functional HIV-1 specific CD8 T-cell responses for the evaluation and prioritization of new HIV-1 vaccine candidates. We previously established a viral inhibition assay (VIA) that measures the ability of vaccine-induced CD8 T-cell responses to inhibit viral replication in autologous CD4 T cells. In this assay, viral replication is determined by measuring p24 in the culture supernatant. Here we describe the development of a novel VIA, referred to as IMC LucR VIA that exploits replication-competent HIV-1 infectious molecular clones (IMCs) in which the complete proviral genome is strain-specific and which express the Renilla luciferase (LucR) gene to determine viral growth and inhibition. The introduction of the luciferase readout does provide significant improvement of the read out time. In addition to switching to the LucR read out, changes made to the overall protocol resulted in the miniaturization of the assay from a 48 to a 96-well plate format, which preserved sample and allowed for the introduction of replicates. The overall assay time was reduced from 13 to 8 days. The assay has a high degree of specificity, and the previously observed non-specific background inhibition in cells from HIV-1 negative volunteers has been reduced dramatically. Importantly, we observed an increase in positive responses, indicating an improvement in sensitivity compared to the original VIA. Currently, only a limited number of "whole-genome" IMC-LucR viruses are available and our efforts will focus on expanding the panel to better evaluate anti-viral breadth. Overall, we believe the IMC LucR VIA provides a platform to assess functional CD8 T-cell responses in large-scale clinical trial testing, which will enhance the ability to select the most promising HIV-1 vaccine candidates capable of controlling HIV-1 replication in vivo.

We performed a molecular phylogenetic study on HIV-1 polymerase sequences of men who have sex with men (MSM) and heterosexual patient samples in Kenya to characterize any observed HIV-1 transmission networks. HIV-1 polymerase sequences were obtained from samples in Nairobi and coastal Kenya from 84 MSM, 226 other men, and 364 women from 2005 to 2010. Using Bayesian phylogenetics, we tested whether sequences clustered by sexual orientation and geographic location. In addition, we used trait diffusion analyses to identify significant epidemiological links and to quantify the number of transmissions between risk groups. Finally, we compared 84 MSM sequences with all HIV-1 sequences available online at GenBank. Significant clustering of sequences from MSM at both coastal Kenya and Nairobi was found, with evidence of HIV-1 transmission between both locations. Although a transmission pair between a coastal MSM and woman was confirmed, no significant HIV-1 transmission was evident between MSM and the comparison population for the predominant subtype A (60%). However, a weak but significant link was evident when studying all subtypes together. GenBank comparison did not reveal other important transmission links. Our data suggest infrequent intermingling of MSM and heterosexual HIV-1 epidemics in Kenya.

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To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs).

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To estimate the potential impact of an HIV/AIDS Vaccine in Kenya. Design: The Kenyan HIV/AIDS epidemic was modeled using the most current data from national sources including epidemiology and behavioral surveillance. The model’s baseline projection was validated against adult HIV prevalence at antenatal clinics and ge- neral population surveys. The model was used to analyze the effects of scaling up current pre- vention programs and adding potential HIV vac- cines with varying levels of effectiveness and coverage. Results: Even with full scale-up of currently available prevention, care and treat- ment programs, new infections will continue to burden Kenya. The introduction of a partially ef- fective AIDS vaccine could significantly alter the trajectory of the epidemic. Conclusion: The game changing impact that an AIDS vaccine could have on the AIDS epidemic in Kenya under- scores the importance of sustaining political support and financial investment to accelerate HIV/AIDS vaccine research and development.

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HIV rapid tests (RT) are a quick and non-technically demanding means to perform HIV voluntary counselling and testing (VCT) but understanding their limitations is vital to delivering quality VCT. Objective: To determine the sensitivity and specificity of HIV rapid tests used for research and voluntary counselling and testing at four sites in East Africa. Design: Cross-sectional study. Setting: Masaka District, Uganda; a sugar plantation in Kakira, Uganda; Coastal Villages in the Kilifi District of Kenya; and the Urban slum of Kangemi located West of Nairobi, Kenya. Subjects: Six thousands two hundred and fifty five consenting volunteers were enrolled into the study, and 675 prevalent HIV infections were identified. Results: The RT sensitivity tended to be high for all assays at all sites (97.63-100%) with the exception of the Uni-Gold assay (90.24% in Kangemi, 96.58% in Kilifi). Twenty four RT results were recorded as ‘weak positives’, 22 (92%) of which were negative by ELISA. There was a high rate of RT false positives in Uganda (positive predictive values ranging from 45.70% to 86.62%). Conclusions: The sensitivity and specificity of the RT varied significantly across sites. The rate of RT misclassification in Uganda suggests that a multiple test algorithm may be preferable to a single test as screener for HIV VCT.

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To determine the occurrence of L. pneumophila among pneumonia patients at Kenyatta National Hospital and any association with possible risk factors. Design: A cross- sectional descriptive study. Setting: The study was conducted from March to June 2007, at the medical ward of Kenyatta National Hospital. Analysis of samples was done at the University of Nairobi Institute of Tropical and Infectious Diseases (UNITID) serology laboratories. Subjects: All adult patients who were admitted to the medical ward of the hospital with a provisional diagnosis of pneumonia. Results: The study indicated that up to 9.2% (11 out of 120) of the pneumonia patients admitted at the hospital were infected with L.pneumophila. At a confidence limit of 0.05, there was statistical significance in the number of pneumonia patients infected with L. pneumophila and exposure to air conditioners (p= 0.003). Twenty two point five eight per cent of patients who were exposed to air conditioners were positive for L. pneumophila urinary antigen. There was a statistical significance between exposure to air conditioners and location of work area (p= 0.001)). Thirty eight point four six per cent of those who worked indoors were exposed to air conditioners at their places of work. There was also statistical significance in the number of pneumonia patients infected with L. pneumophila and a history of a past or concurrent respiratory illness (p= 0.021). Conclusion: Exposure to air conditioners and a history of past or concurrent respiratory illness were found to predispose one to infection. This should raise the index of suspicion among clinicians as they obtain a patient’s medical history. Most of those exposed to air conditioners are exposed at their places of work in urban centres, hence the need for health education and public awareness on routine inspection and maintenance of such facilities. There is need for a larger multi-centre study on the prevalence of infection by L. pneumophila in pneumonia patients (both community acquired and nosocomial), existence of co- infection and the antibiotic susceptibility of isolated organisms

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Cytokine flow cytometry (CFC) or intracellular cytokine staining (ICS) can quantitate antigen-specific T cell responses in settings such as experimental vaccination. Standardization of ICS among laboratories performing vaccine studies would provide a common platform by which to compare the immunogenicity of different vaccine candidates across multiple international organizations conducting clinical trials. As such, a study was carried out among several laboratories involved in HIV clinical trials, to define the inter-lab precision of ICS using various sample types, and using a common protocol for each experiment (see additional files online). Results: Three sample types (activated, fixed, and frozen whole blood; fresh whole blood; and cryopreserved PBMC) were shipped to various sites, where ICS assays using cytomegalovirus (CMV) pp65 peptide mix or control antigens were performed in parallel in 96-well plates. For one experiment, antigens and antibody cocktails were lyophilised into 96-well plates to simplify and standardize the assay setup. Results (CD4+cytokine+ cells and CD8+cytokine+ cells) were determined by each site. Raw data were also sent to a central site for batch analysis with a dynamic gating template. Mean inter-laboratory coefficient of variation (C.V.) ranged from 17–44% depending upon the sample type and analysis method. Cryopreserved peripheral blood mononuclear cells (PBMC) yielded lower inter-lab C.V.'s than whole blood. Centralized analysis (using a dynamic gating template) reduced the inter-lab C.V. by 5–20%, depending upon the experiment. The inter-lab C.V. was lowest (18–24%) for samples with a mean of >0.5% IFNγ + T cells, and highest (57–82%) for samples with a mean of <0.1% IFNγ + cells. Conclusion: ICS assays can be performed by multiple laboratories using a common protocol with good inter-laboratory precision, which improves as the frequency of responding cells increases. Cryopreserved PBMC may yield slightly more consistent results than shipped whole blood. Analysis, particularly gating, is a significant source of variability, and can be reduced by centralized analysis and/or use of a standardized dynamic gating template. Use of pre-aliquoted lyophilized reagents for stimulation and staining can provide further standardization to these assays.

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BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. Interpretation: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1. PIP: A cohort study conducted in 1985-94 among 424 prostitutes from Nairobi, Kenya, who were initially human immunodeficiency virus (HIV)-1 seronegative, tended to provide support for the observation that some individuals in highly exposed populations may be resistant to infection. During the 10-year study period, 239 of these women seroconverted. The overall HIV-1 incidence was 42/100 person-years. After the first 2 years of follow up, in which the majority of seroconversions occurred, HIV-1 prevalence reached a plateau and then began a steep decline. To determine whether the risk of HIV-1 infection declined over time as a result of the selection of resistance, incidence rates among women with less than 3 years' versus more than 3 years' duration of prostitution were compared for 1989-93. An increasing protective effect for each seronegative year of exposure was observed. The estimated cumulative protective effect for women practicing prostitution from 1984-93 and remaining seronegative, compared to women who entered prostitution in 1994, was over 100-fold. To rule out the possibility that the decrease in seroconversion with duration of exposure reflected differences in sexual behavior or immunity to sexually transmitted diseases that facilitate HIV transmission, Cox proportional hazards modelling was performed. The weighted duration of prostitution was independently associated with a decreased risk of seroconversion. Each weighted year of exposure resulted in a 1.2-fold decrease in risk. Women who seroconverted were more likely to report 1 or more regular partners and to use condoms with these partners than their counterparts who remained seronegative. Elucidation of the protective mechanisms and the factors mediating the development of immunity against HIV-1 could be important to HIV-1 vaccine research.

The progression of HIV-related disease from infection to death is represented as a staged Markov model. Transitions between stages are considered reversible. The model is fitted to data from a cohort of African prostitutes by means of maximum likelihood. It appears that the progression to symptomatic disease (Centers for Disease Control stage IV) in this population is considerably more rapid than that reported from studies in Western countries. PIP: Identifying the incubation period of HIV infection is important for individual prognoses, for developing and testing intervention strategies, for determining the reproductive rate of the disease, and for prevalence of the disease. Mathematical modeling of HIV infection in Africa is necessitated because the disease is more widespread and the immune system is constantly active due to the exposure to diseases such as malaria and tuberculosis. The Markov model for this analysis was selected because parametric estimation is not based on the time a stage is entered, but on the duration between observations and the stages at the time of observation. The HIV infected female prostitutes in the Pumwani area of Nairobi, Kenya (a population primarily of Tanzanian origin) have been identified as a study population since 1985, and seen every 6 months in clinic, or as needed. Data are constricted by the movement out of the area in the end stage of disease, which is only partially solved by tracking with community health workers. The stages identified in incubation estimation are stage 1: seropositive but symptom free (CDC stage II); stage 2: generalized lymphadenopathy (CDC stage III); stage 3: symptomatic disease (CDC stage IV); and stage 4: death. Data reflect the movement back and forth between stage 1 and 2, between 2 and 3, so the model is not a pure Longini model but rather a timed homogeneous staged model with reversible stages called transition parameters computed in a numerical differentiation. The Fortran computer program for the analyses is available from the authors. The results suggest a quick transition between seroconversion and lymphadenopathy (2.4 months) and unlikely reversal, with the mean waiting time until passage to stage 3 is approximately 2.6 years and conversions are common. Since opportunistic infections are treatable, this makes sense. Assuming a correct model, the estimation of the transition time of 20 months of h34 value of .01 and .05, the mean passage time from stage 1, 2, 3 to 4 (death) is 9.1, 8.9, and 6.2 years 12.9, 12.7, and 10.1 years respectively. The implications are that 1) when infectiousness is hypothesized to be not uniform, peak infectivity occurs earlier in Africa than in the West at least among prostitutes, or 2) if infectivity is constant throughout the incubation period, then HIV transmission must be higher in Africa to explain the high rate of infection