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T cell responses against HIV-1 have been identified in a number of exposed uninfected populations. We hypothesized that the ability to mount an effective T cell response is partly determined by the human leucocyte antigens (HLA) phenotype of the individual. We examined whether certain HLA supertypes were associated with differential HIV-1 susceptibility in sexually exposed adults and in the setting of mother to child HIV-1 transmission. By multivariate analysis, decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related class I HLA alleles (A2/6802 supertype) in sexually exposed adults (Hazard ratio=0.42, 95% confidence intervals (CI): 0.22–0.81, P =0.009) and perinatally exposed infants (Odds ratio=0.12, 95% CI: 0.03–0.54, P =0.006). The alleles in this HLA supertype are known in some cases, to present the same peptide epitopes (termed ‘supertopes’), for T cell recognition. The identification of HIV-1 supertopes, which are associated with protection from HIV-1 infection, has important implications for the application of epitope-based HIV-l vaccines in a variety of racial groups.

Neisseria gonorrhoeae cervicitis and human immunodeficiency virus (HIV) type 1 frequently coinfect core transmitter populations, such as female sex workers. Gonococcal cervicitis is associated with increased viral shedding and plasma viremia in HIV-1-infected women and increased HIV-1 susceptibility in uninfected women. We studied the influence of gonococcal cervicitis on CD8(+) interferon (IFN)-gamma responses to HIV-1 and cytomegalovirus (CMV) epitopes in HIV-1-infected and in highly-exposed, persistently seronegative (HEPS) female sex workers. In HIV-1-infected women, gonococcal cervicitis was associated with reduced IFN-gamma responses in bulk CD8(+) lymphocyte populations, and intracellular cytokine staining, combined with class I major histocompatibility complex (MHC)-peptide tetramer studies, demonstrated reduced IFN-gamma production by HIV-1 epitope-specific CD8(+) lymphocytes. In HEPS sex workers, cervicitis was associated with the transient loss of systemic HIV-1-specific CD8(+) responses and with reduced function of CMV-specific CD8(+) lymphocytes. Impaired function of virus-specific CD8(+) lymphocytes may partly explain the deleterious effects of gonococcal cervicitis on HIV-1 immune control and susceptibility.

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime–boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime–MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

HIV-specific cytotoxic T-lymphocytes (CTL) are believed to play a key part in the control of virus levels throughout HIV infection. An important goal of a potential prophylactic vaccine against HIV is therefore to elicit a strong CTL response which is broadly cross-reactive against a diverse range of HIV strains. We have detected HIV-specific CTL in two groups of highly-exposed but persistently seronegative female sex workers in Africa which show extensive cross-reactivity between different viral sequences. In a small group of women exposed to both HIV-1 and HIV-2 in Gambia, studied over 4 years, we have repeatedly detected HLA-B35-restricted CTL which exhibit cross-reactivity between the HIV-1 and HIV-2 sequences of the CTL epitopes. In women with particularly intense exposure to what are likely to be multiple clades of HIV-1 in Nairobi Kenya, we have detected CTL directed towards epitopes conserved between HIV-1 clades. In neither group is there any evidence that variation in CCR5 sequence or expression is responsible for their apparent resistance to HIV infection. However, in seropositive donors from Oxford infected with African strains of HIV-1, we have defined CTL responses which are specific for particular clades and have mapped some unique A clade CTL epitopes, together with others to highly-conserved regions of the virus. Further information about the extent of cross-reactive CTL immunity will be important for future vaccine design and evaluation.

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-naive 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.

Background: The host immune response against mucosally acquired pathogens maybe 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 ill 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.

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.

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 IFN gamma-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 IFN gamma 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.

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 Tcell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha and beta (MIP-1αand -β) 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.

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.

Observational studies have suggested that low serum β-carotene concentrations may influence HIV-1 disease progression. However, randomized trials have not demonstrated beneficial effects of β-carotene supplementation. To understand this discrepancy, we conducted a cross-sectional study among 400 HIV-1-seropositive women in Mombasa, Kenya, to correlate serum β-carotene concentrations with several measures of HIV-1 disease severity. β-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, β-carotene concentrations below the median were associated with elevated CRP (>10mg/l, adjusted odds ratio [aOR] 3.32, 95% confidence interval [CI] 1.99–5.53, P 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 β-carotene supplementation in HIV-1-seropositive individuals, these results suggest that low β-carotene concentrations primarily reflect more active HIV-1 infection rather than a deficiency amenable to intervention.

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.

Cross-sectional analyses have associated vitamin A deficiency with genital shedding of herpes simplex virus (HSV) among human immunodeficiency virus type 1 (HIV-1)-infected women. A randomized clinical trial of vitamin A supplementation given daily for 6 weeks was conducted among 376 women in Mombasa, Kenya, who were coinfected with HSV-2 and HIV-1. At follow-up, there was no significant difference in the detection of genital HSV DNA between women receiving vitamin A supplementation and women receiving placebo (40% vs. 44%, respectively; P = .5) Among women shedding HSV, there was no significant difference in the mean HSV DNA quantity between the group that received vitamin A supplementation and the group that received placebo (4.51 vs. 4.67 log10 copies/swab; P = .6). HSV shedding was associated with significantly higher vaginal and cervical HIV-1 shedding, even after controlling for the plasma HIV-1 load and the CD4 count. Vitamin A supplementation is unlikely to decrease HSV shedding and infectivity.

Health care-seeking behavior for sexually transmitted diseases (STDs) is important in STD/HIV control. The goal of this study was to describe the proportion seeking care patient delay and choice of provider among men and women with STD-related complaints in Nairobi Kenya. A population-based questionnaire was administered in 7 randomly selected clusters (small geographic areas covering approximately 150 households each). Of the 291 respondents reporting complaints 20% of men versus 35% of women did not seek care mainly because symptoms were not considered severe symptoms had disappeared or as a result of lack of money. Of those who sought care women waited longer than men (41 vs. 16 days). Most men and women went to the private sector (72% and 57% respectively) whereas the informal sector was rarely visited (13% and 16% respectively). Relatively more women visited the government sector (28% vs. 15%). Because women were mostly monogamous they did not relate their complaints to sexual intercourse which hampered prompt care-seeking. Women should be convinced to seek care promptly eg through health education in communities. (authors)

Invasive cervical cancer (ICC) is the leading cause of cancer-related death among women in developing countries. Population-based cytologic screening and early treatment does reduce morbidity and mortality associated with cervical cancer. Some of the factors related to the success of such a program include awareness about cervical cancer and its screening. The objective of this study was to assess knowledge and practice about cervical cancer and Pap smear testing among cervical cancer and noncancer patients using a structured questionnaire to obtain information. Fifty-one percent of the respondents were aware of cervical cancer while 32% knew about Pap smear testing. There were no significant differences in knowledge between cervical cancer and noncancer patients. Health care providers were the principal source of information about Pap testing (82%). Only 22% of all patients had had a Pap smear test in the past. Patients aware of cervical cancer were more likely to have had a Pap smear test in the past. The level of knowledge is low among ICC and noncancer patients. There is need to increase the level of knowledge and awareness about ICC and screening among Kenyan women to increase uptake of the currently available hospital screening facilities.

To determine the association between invasive cervical cancer (ICC) and HIV infection in Kenyan women.Case-control, with ICC patients as cases, and women with uterine fibroids as controls.Medical and socio-demographic data were collected from 367 ICC patients, and 226 women with fibroids. After informed consent, HIV testing was done.ICC patients were older than fibroid patients (48 versus 41 years; P0.001), with an HIV seroprevalence of 15% and 12% respectively (P0.05). However, cases younger than 35 years were 2.6-times more likely to be HIV positive than controls of similar age [35% versus 17%; odds ratio (OR), 2.6; P = 0.043]. ICC HIV-seropositive patients were, on average, 10 years younger than HIV-seronegative patients (40 versus 50 years; P0.001). Eighty per cent of HIV-seropositive and 77% of HIV-seronegative ICC patients were in FIGO stage IIb or above. However, the odds of having poorly differentiated tumours was three times higher for HIV-seropositive than for HIV-seronegative ICC patients (77% versus 52%; OR, 3.1; P = 0.038) after adjusting for histological cell type and clinical stage. Mean CD4 cell count was 833 x 10(6) cells/l in ICC and 1025 x 10(6) cells/l in fibroid patients (P = 0.001).Young women with ICC were more often HIV infected than women with fibroids of the same age groups. HIV infection was associated with poor histological differentiation of the tumours. These findings suggest an accelerated clinical progression of premalignant cervical lesions to ICC in HIV-infected women.

To describe the role of traditional healers in STD case management, in-depth interviews were held with 16 healers (seven witchdoctors, five herbalists and four spiritual healers) in four slum areas in Nairobi, Kenya. All healers believed that STDs are sexually transmitted and recognized the main symptoms. The STD-caseload varied largely, with a median of one patient per week. Witchdoctors and herbalists dispensed herbal medication for an average of seven days, whereas spiritual healers prayed. Thirteen healers gave advice on sexual abstinence during treatment, 11 on contact treatment, four on faithfulness and three on condom use. All healers asked patients to return for review and 13 reported referring patients whose conditions persist to public or private health care facilities. Thus, traditional healers in Nairobi play a modest but significant role in STD management. Their contribution to STD health education could be strengthened, especially regarding the promotion of condoms and faithfulness.

Among HIV-1-infected individuals, vitamin A deficiency has been associated with faster disease progression and greater infectivity in observational studies, but randomized clinical trials have shown no effect of vitamin A supplementation. We conducted a cross-sectional study of 400 HIV-1-infected and 200 HIV-1-uninfected women in Mombasa, Kenya to examine the relations between vitamin A deficiency (serum retinol30 microg/dL) and HIV-1 status, HIV-1 disease stage, and the acute phase response (serum C-reactive proteinor=10 mg/L and/or alpha1-acid glycoproteinor=1.2 g/L). Among the HIV-1-infected women, the effect of vitamin A supplementation was examined in a randomized trial. Vitamin A deficiency was independently associated with HIV-1 infection (OR = 2.7, 95% CI: 1.9-4.0) and the acute phase response (OR = 2.8, 95% CI: 1.9-4.1). Among HIV-1-infected women, vitamin A deficiency and the acute phase response were associated with each other and were both independently associated with higher HIV-1 plasma viral load and lower CD4 count. HIV-1-infected women having an acute phase response had no increase in serum vitamin A levels after supplementation. Serum levels increased significantly among women without an acute phase response, although not to normal levels among women who were deficient at baseline. Among HIV-1-infected individuals, it is likely that low serum vitamin A concentrations reflect more active infection and the acute phase response. These results provide possible explanations for the disparity between observational studies and randomized trials of vitamin A for HIV-1 infection.

Observational studies have associated vitamin A deficiency with vaginal shedding of human immunodeficiency virus (HIV) type 1-infected cells and mother-to-child HIV-1 transmission. To assess the effect of vitamin A supplementation on vaginal shedding of HIV-1, a randomized, double-blind, placebo-controlled trial of 6 weeks of daily oral vitamin A (10,000 IU of retinyl palmitate) was conducted among 400 HIV-1-infected women in Mombasa, Kenya. At follow-up, there was no statistically significant difference in the prevalence of HIV-1 DNA (18% vs. 21%, P=.4) or the quantity of HIV-1 RNA (3.12 vs. 3.00 log(10) copies/swab, P=1.0) in vaginal secretions of women receiving vitamin A, compared with women receiving placebo. No significant effect of supplementation on plasma HIV-1 load or CD4 or CD8 cell counts was observed, and no effect was seen among women who were vitamin A deficient at baseline. Vitamin A supplementation is unlikely to decrease the infectivity of women infected with HIV-1.

A clearer understanding of HIV-1 specific immune responses in highly-exposed, persistently seronegative (HEPS) subjects is important in developing models of HIV-1 protective immunity. HIV-1 specific cytotoxic T-lymphocytes (CTL) have been described in a cohort of HEPS Kenyan sex workers, and recent work has further elucidated these responses. CTL specific for HIV-1 Env were found in the blood of over half the sex workers meeting criteria for HIV resistance, and in some women recognized unmapped epitopes. The proportion of women with Env -specific CTL increased with the duration of uninfected HIV exposure, suggesting that these responses were acquired over time. CD8+ lymphocyte responses directed against predefined HIV-1 CTL epitopes from various HIV-1 genes were found in the blood and genital tract of >50% resistant sex workers, at a ten-fold lower frequency than in infected subjects. The epitope specificity of CD8+ responses differs between HEPS and HIV infected women, and in HEPS the maintenance of responses appears to be dependent on persistent HIV exposure. Several HIV-1 ‘resistant’ sex workers have become HIV infected over the past 6 years, possibly related to waning of pre-existing HIV-specific CTL, and infection has often been associated with a switch in the epitope specificity of CD8+ responses. These findings suggest that vaccine-induced protective HIV immunity is a realistic goal, but that vaccine strategies of boosting or persistent antigen may be necessary for long-lived protection.

Although HIV-specific cellular immune responses are found in a number of HIV highly-exposed, persistently seronegative (HEPS) cohorts, late seroconversion can occur despite pre-existing cytotoxic T lymphocytes (CTL), suggesting that a protective HIV vaccine may need to induce a broader range of HIV-specific immune responses. Low levels of HIV-specific IgA have been found in the genital tract and plasma of the majority of Nairobi HEPS sex workers and appeared to be independent of HIV-specific cellular responses. IgA purified from genital tract, saliva and plasma of most HEPS sex workers were able to neutralize infection of PBMC by a primary (NSI) clade B HIV isolate, as well as viral isolates from clades A and D, which predominate in Kenya. In addition, these IgA were able to inhibit transcytosis of infective HIV virions across a transwell model of the human mucosal epithelium in an HIV-specific manner. Preliminary work in other HEPS cohorts has suggested the recognition of different gp41 epitopes in HEPS and HIV-infected subjects. Although present at low levels, these IgA demonstrated cross-clade neutralizing activity and were able to inhibit HIV mucosal transcytosis, suggesting an important functional role in protection against HIV infection.

Objective: To assess the association between vaginal douching and sexually transmitted infections (STI) among a group of female sex workers (FSWs) in Nairobi, Kenya. Methods: This study was part of a randomised, placebo controlled trial of monthly prophylaxis with 1 g of azithromycin to prevent STIs and HIV infection in a cohort of Nairobi FSWs. Consenting women were administered a questionnaire and screened for STIs. Results: The seroprevalence of HIV-1 among 543 FSWs screened was 30%. HIV infection was significantly associated with bacterial vaginosis (BV), trichomoniasis, gonorrhoea, and the presence of a genital ulcer. Regular douching was reported by 72% of the women, of whom the majority inserted fluids in the vagina, generally after each sexual intercourse. Water with soap was the fluid most often used (81%), followed by salty water (18%), water alone (9%), and a commercial antiseptic (5%). Douching in general and douching with soap and water were significantly associated with bacterial vaginosis (p = 0.05 and p = 0.04 respectively). There was a significant trend for increased frequency of douching and higher prevalence of BV. There was no direct relation observed between douching and risk for HIV infection or other STIs. Conclusion: The widespread habit of douching among African female sex workers was confirmed. The association between vaginal douching and BV is of concern, given the increased risk of HIV infection with BV, which has now been shown in several studies. It is unclear why we could not demonstrate a direct association between douching and HIV infection. Further research is required to better understand the complex relation between douching, risk for bacterial vaginosis, and risk for HIV and other STIs.

Background Low-dose nonoxynol-9 products have a potential advantage of reduced toxicity. However, little is known about their efficacy in reducing the incidence of sexually transmitted diseases (STDs). Goal To determine the effect that an intravaginal gel containing 52.5 mg of nonoxynol-9 has on the acquisition of STDs in a cohort of HIV-1-seronegative female sex workers in Mombasa, Kenya. Study design A randomized double-blind placebo controlled trial was performed. Results In this study, 139 women were randomized to the nonoxynol-9 group and 139 to the placebo group. No significant differences were found between the two study groups in terms of safety outcomes and reported symptoms, except for a lower incidence of vaginal erythema in the nonoxynol-9 group. There was a significantly higher incidence of gonorrhea in the nonoxynol-9 group than in the placebo group. No significant differences were observed between the groups for acquisition of Candida, trichomonas, bacterial vaginosis, C trachomatis, syphilis, or HIV-1, although the statistical power to detect differences for some of these STDs was limited. Conclusions In this randomized placebo-controlled trial of a low-dose nonoxynol-9 gel, a significantly higher incidence of gonorrhea was found in the nonoxynol-9 group, but no significant differences between the groups were found for Candida, trichomonas, bacterial vaginosis, C trachomatis, syphilis, or HIV-1.

Background. Reference lymphocyte subset values for African children are lacking. This study documents these values as well as their alterations associated with perinatal and postnatal HIV-1 transmission and with protection from HIV-1 infection. Methods. Lymphocyte subsets were determined for HIV-1-seronegative nonpregnant women and their children (controls) and for uninfected, perinatally infected and postnatally infected children born to HIV-1-seropositive mothers in Nairobi, Kenya. The mean, median and 5th and 95th percentile values for CD4 + and CD8 + lymphocyte counts and percentages were determined and compared at the age ranges birth to 3 months, 4 months to 1 year, yearly from 1 to 5 years and from 6 to 10 years of age. Results. Among control children counts differed from published values of other populations. In all age ranges, whereas the absolute values were significantly higher than adult values, the percentages were significantly lower. Children perinatally infected with HIV-1 had clearly distinguishable differences in lymphocyte subset percentages by 3 months of age, when the median CD4 + percentage was 27.9% (5th to 95th percentile, 25.7 to 30.1%) for infected vs. 35.9% (33.3 to 38.7%) for uninfected and 39.9% (37.8 to 42.2%) for control children, P < 0.001; whereas the median CD8 + percentage was 37.0% (33.1 to 41.0%) for infected vs. 27.5% (24.2 to 30.8%) for uninfected and 27.5% (24.2 to 30.8%) for control children, P = 0.001. Differences between uninfected and control children disappeared after 1 year of age. Conclusions. Normal lymphocyte subset values among African children differ from those in other populations. Significant differences are detectable by 3 months of age in CD4 + and CD8 + lymphocyte percentages among perinatally infected infants, which may be useful as an adjunct in diagnosis. Transient differences observed among HIV-1-exposed but uninfected infants could reflect a successful immune response to HIV-1 challenge.

Certain HLAs may, in part, account for differences in human immunodeficiency virus type 1 (HIV-1) susceptibility by presenting conserved immunogenic epitopes for T cell recognition. The HLA supertype A2/6802 is associated with decreased susceptibility to HIV-1 among sex workers. The alleles in this supertype present the same HIV-1 peptide epitopes for T cell recognition in some cases. This study sought to determine whether the HLA A2/6802 supertype influenced HIV-1 transmission in a prospective cohort of HIV-1‐infected mothers and children in Kenya. Decreased perinatal HIV-1 infection risk was strongly associated with possession of a functional cluster of related HLA alleles, called the A2/6802 supertype (odds ratio, 0.12; 95% confidence interval, 0.03‐0.54; ). This effect was independent of the protective P p .006 effect of maternal-child HLA discordance. These data provide further evidence that HLA supertypes are associated with differential susceptibility to HIV-1 transmission.

To determine the effects of plasma, genital, and breast milk human immunodeficiency virus type 1 (HIV-1) and breast infections on perinatal HIV-1 transmission, a nested case-control study was conducted within a randomized clinical trial of breast-feeding and formula feeding among HIV-1-seropositive mothers in Nairobi, Kenya. In analyses comparing 92 infected infants with 187 infants who were uninfected at 2 years, maternal viral RNA levels >43,000 copies/mL (cohort median) were associated with a 4-fold increase in risk of transmission (95% confidence interval [CI], 2.2-7.2). Maternal cervical HIV-1 DNA (odds ratio [OR], 2.4; 95% CI, 1.3-4.4), vaginal HIV-1 DNA (OR, 2.3; 95% CI, 1.1-4.7), and cervical or vaginal ulcers (OR, 2.7; 95% CI, 1.2-5.8) were significantly associated with infant infection, independent of plasma virus load. Breast-feeding (OR, 1.7; 95% CI, 1.0-2.9) and mastitis (relative risk [RR], 3.9; 95% CI, 1.2-12.7) were associated with increased transmission overall, and mastitis (RR, 21.8; 95% CI, 2.3-211.0) and breast abscess (RR, 51.6; 95% CI, 4.7-571.0) were associated with late transmission (occurring >2 months postpartum). Use of methods that decrease infant exposure to HIV-1 in maternal genital secretions or breast milk may enhance currently recommended perinatal HIV-1 interventions.

Objective: To determine whether cervical mucosal shedding of HIV-1 RNA and HIV-1 infected cells decreases following successful treatment of cervicitis. Design: Prospective interventional study. Setting: Sexually Transmitted Infections Clinic, Coast Provincial General Hospital, Mombasa, Kenya. Participants: Thirty-six HIV-1 seropositive women with cervicitis: 16 with Neisseria gonorrhoeae, seven with Chlamydia trachomatis, and 13 with non-specific cervicitis. Interventions: Treatment of cervicitis. Main outcome measures: Levels of total (cell-free and cell-associated) HIV-1 RNA and presence of HIV-1 DNA (a marker for infected cells) in cervical secretions before and after resolution of cervicitis. Results: After treatment of cervicitis, the median HIV-1 RNA concentration in cervical secretions was reduced from 4.05 to 3.24 log 10 copies/swab (P = 0.001). Significant decreases in cervical HIV-1 RNA occurred in the subgroups with N. gonorrhoeae (3.94 to 3.28 log 10 copies/swab; P= 0.02) and C. trachomatis (4.21 to 3.19 log 10 copies/swab; P = 0.02). Overall, the prevalence of HIV-1 infected cells in cervical secretions also decreased after treatment, from 67% to 42% (odds ratio, 2.8; 95% confidence interval, 1.3-6.0; P= 0.009). Detection of infected cells was associated with higher mean HIV-1 RNA levels (4.04 versus 2.99 log 10 copies/swab; P < 0.0001). Conclusions: Effective treatment of cervicitis resulted in significant decreases in shedding of HIV-1 virus and infected cells in cervical secretions. Treatment of sexually transmitted diseases may be an important means of decreasing the infectivity of HIV-1 seropositive women by reducing exposure to HIV-1 in genital secretions.

Quality of health education during STD case management in Nairobi was assessed in 142 healthcare facilities, through interviews of 165 providers, observation of 441 STD patients managed by these providers, and 165 visits of simulated patients. For observations, scores were high for education on contact treatment (74-80%) and compliance (83%), but unsatisfactory for counselling (52%) and condom promotion (20-41%). The World Health Organization (WHO) indicator for STD case management Prevention Indicator 7 (PI7) (condom promotion plus contact treatment) was poor (38%). Public clinics strengthened for STD care generally performed best, whereas pharmacies and mission clinics performed worst. Compared with observations, scores were higher during interviews and lower during simulated patient visits, indicating that knowledge was not fully translated into practice. Interventions to improve the presently unsatisfactory service quality would be wide distribution of health education materials, ongoing training and supervision of providers, implementation of STD management checklists, and the introduction of pre-packaged kits for STD management.

Summary The goal of the present study was to determine whether there were HIV-1 specific cellular immune responses among a subgroup of women within a cohort of Nairobi prostitutes (n = 1800) who, despite their intense sexual exposure to HIV-1, are epidemiologically resistant to HIV-1 infection. Of the 80 women defined to be resistant, 24 were recruited for immunological evaluation. The HIV-1-specific T-helper responses were determined by IL-2 production following stimulation with HIV-1 envelope peptides and soluble gp120. Cytotoxic T lymphocyte responses were determined by lysis of autologous EBV-transformed B cell lines infected with control vaccinia virus or recombinant vaccinia viruses containing the HIV-1 structural genes env, gag and pol. Resistant women had significantly increased HIV-1 specific T-helper responses, as determined by in vitro IL-2 production to HIV-1 envelope peptides and soluble glycoprotein 120, compared with low-risk seronegative and HIV-1-infected controls (P ≤ 0.01, Student’s t-test). Seven of the 17 (41%) resistant women showed IL-2 stimulation indices ♢ 2.0. HIV-1specific CTL responses were detected among 15/22 (68.2%) resistant women compared with 0/12 low-risk controls (Chi-squared test, P < 0.001). In the two resistant individuals tested, the CTL activity was mediated by CD8 + effectors. Many HIV-1-resistant women show evidence of HIV-1-specific T-helper and cytotoxic responses. These data support the suggestion that HIV-1-specific T-cell responses contribute to protection against HIV-1 infection.

Objective: To characterize functional properties of HIV-specific IgA in samples representing both systemic and mucosal compartments of HIV-1 highly exposed persistently seronegative (HEPS) individuals. Methods: IgA was purified from plasma and mucosal samples from HEPS individuals and tested for the ability to neutralize infection of peripheral blood mononuclear cells (PBMC) by a non-syncytium inducing HIV-1 (clade B) primary isolate. None of these individuals had measurable HIV-1-specific IgG. Results: HIV-1-specific neutralizing activity of the purified IgA from plasma (n = 15), saliva (n = 15) and cervicovaginal fluid (CVF) (n = 14) were found in the majority of samples (73, 73 and 79%, respectively). In contrast, plasma, saliva and CVF samples of low-risk, uninfected HIV-seronegative individuals lacked neutralizing IgA, with the exception of two out of 34 (6%) saliva samples. Conclusion: Mucosal and plasma IgA from HEPS individuals can neutralize HIV-1 infection.

In Kenya sexually transmitted disease (STD) clinics care for large numbers of patients with STD-related signs and symptoms. Yet the etiologic fraction of the different STD pathogens remains to be determined particularly in women. The aim of the study was to determine the prevalence of STDs and of cervical dysplasia and their risk markers among women attending the STD clinic in Nairobi. A cross-section of women were interviewed and examined; samples were taken. The mean age of 520 women was 26 years 54% had a stable relationship 38% were pregnant 47% had ever used condoms (1% as a method of contraception) 11% reported multiple partners in the previous 3 months and 32% had a history of STDs. The prevalence of STDs was 29% for HIV type 1 35% for candidiasis 25% for trichomoniasis 16% for bacterial vaginosis 6% for gonorrhea 4% for chlamydia 6% for a positive syphilis serology 6% for genital warts 12% for genital ulcers and 13% for cervical dysplasia. Factors related to sexual behavior especially the number of sex partners were associated with several STDs. Gonorrhea bacterial vaginosis cervical dysplasia and genital warts or ulcers were independently associated with HIV infection. Partners of circumcised men had less-prevalent HIV infection. Most women reported low-risk sexual behavior and were likely to be infected by their regular partner. HIV and STD prevention campaigns will not have a significant impact if the transmission between partners is not addressed. (authors)

OBJECTIVES: The main purpose of this study is to compare sexually transmitted disease (STD) prevalence in cohorts of women with and without access to female condoms. METHODS: Six matched pairs of communities were identified from Kenya tea, coffee and flower plantations. One community within each pair was randomly selected to receive the female condom intervention. Approximately 160 eligible women were enrolled at each site. Female condom communities underwent an education program on use of female and male condoms and STDs, comprising group meetings, puppetry and other folk media, and training of clinic service providers and community outreach workers. Control communities received similar information on use of male condoms (freely available at all sites). At baseline, participants were tested for cervical gonorrhea and chlamydia and vaginal trichomoniasis, to be repeated at 6 and 12 months. The study has 80% power to detect a 10% prevalence difference, assuming an aggregate STD prevalence of 20% with 25% loss to follow-up and intracluster correlation of 0.03. RESULTS: Among 1929 women at baseline, the mean age was 33.1 years; 78% had never used a male condom. The prevalences of gonorrhea, chlamydia and trichomoniasis were 2.6%, 3.2% and 20.4%, respectively (23.9% overall). The intracluster correlation based on these data was near zero. CONCLUSIONS: Comparable pairs of study sites have been selected. STD prevalence is sufficiently high, and the variation between sites is acceptably low. The study is feasible as designed.

In Kenya, the median incubation time to AIDS in seroconverting sex workers is 4 years; this incubation time is specific to female sex workers. We studied the influence of acute sexually transmitted infections (STIs) on several immunologic parameters in 32 human immunodeficiency virus type 1 (HIV-1)-positive and 10 HIV-1-negative women sex workers who were followed for 1-5 months. Plasma cytokines, soluble cytokine receptors, CD4 and CD8 T cell counts, and HIV-1 plasma viremia were quantitated before, during, and after episodes of STI. Increases in interleukin (IL)-4, IL-6, IL-10, soluble tumor necrosis factor (TNF)-alpha, and viremia and a decline in CD4(+) T cell counts occurred during gonococcal cervicitis and returned to baseline after treatment. Increases in viremia correlated with increased IL-4 and decreased IL-6 concentrations. Similar changes were seen among women with acute pelvic inflammatory disease. Acute bacterial STI resulted in increased HIV-1 viremia. This may be mediated through increased inflammatory cytokines or through modulation of immune responses that control HIV-1 viremia.

Accurate predictions of HIV-1 incidence in potential study populations are essential for designing HIV-1 vaccine efficacy trials. Little information is available on the estimated incidence of HIV-1 in such populations especially information on incidence over time and incidence while participating in risk-reduction programs. The aim was to examine time trends in HIV-1 incidence in a vaccine preparedness cohort. A prospective cohort study of female prostitutes in Mombasa Kenya was carried out. HIV-1 incidence was determined using open and closed cohort designs. Generalized estimating equations were used to model HIV-1 and sexually transmitted disease (STD) incidence and sexual risk behaviors over time. When analyzed as a closed cohort HIV-1 incidence declined 10-fold during 3 years of follow-up (from 17.4 to 1.7 cases/100 person-years; p < 0.001). More than 50% of the cases of HIV-1 occurred during the first 6 months after enrollment and 73% during the first 12 months. When analyzed as an open cohort HIV-1 incidence density fell during the first 4 calendar years influenced by accumulation of lower risk participants and variations in study recruitment. Significant declines occurred in both STD incidence and high-risk sexual behaviors during follow-up. This study documents a dramatic decline in the risk of HIV-1 infection while participating in a prospective cohort with most seroconversions occurring within 1 year of enrollment. Variations in HIV-1 incidence within high-risk population should be anticipated during the design of vaccine trials. (authors)

Certain human leukocyte antigens, by presenting conserved immunogenic epitopes for T cell recognition, may, in part, account for the observed differences in human immunodeficiency virus type 1 (HIV-1) susceptibility. To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge. These data provide further evidence that resistance to HIV-1 infection in this cohort of sex workers is immunologically mediated.

Objectives: To assess the impact of a syphilis control programme of pregnant women on pregnancy outcome in Kenya. Method: Women who came to deliver to Pumwani Maternity Hospital (PMH) between April 1997 and March 1998 were tested for syphilis. Reactive rapid plasma reagin (RPR) tests were titrated and confirmed with treponema haemagglutination test (TPHA). Equal numbers of RPR and TPHA negative women were enrolled. Antenatal syphilis screening and treatment history were examined from the antenatal cards. Results: Of 22 466 women giving birth, 12 414 (55%) were tested for syphilis. Out of these, 377 (3%) were RPR reactive of whom 296 were confirmed by TPHA. Syphilis seroreactive women had a more risky sexual behaviour and coexistent HIV antibody positivity; 26% were HIV seropositive compared with 11% among syphilis negative mothers. The incidence of adverse obstetric outcome defined as low birth weight and stillbirth, was 9.5%. Syphilis seropositive women had a higher risk for adverse obstetric outcome (OR 4.1, 95% CI 2.4–7.2). Antenatal treatment of RPR reactive women significantly improved pregnancy outcome but the risk of adverse outcome remained 2.5-fold higher than the risk observed in uninfected mothers. Conclusions: These data confirm the adverse effect of syphilis on pregnancy outcome. This study also shows the efficacy of antenatal testing and prompt treatment of RPR reactive mothers on pregnancy outcome. Key Words: syphilis testing; pregnancy outcome; Kenya

The occurrence of clinical manifestations associated with primary human immunodeficiency virus type 1 (HIV-1) infection was evaluated in a prospective cohort study of female sex workers in Mombasa, Kenya. Among 103 women who seroconverted to HIV-1, fever, vomiting, diarrhea, headache, arthralgia, myalgia, skin rash, swollen lymph nodes, extrainguinal lymphadenopathy, inguinal lymphadenopathy, and vaginal candidiasis were noted significantly more frequently at visits in which seroconversion first became evident. Eighty-one percent of seroconverting women had >/=1 of these 11 symptoms or signs. Among 44% of the women, the acute illness was severe enough to prevent them from working. Having >/=2 of 6 selected symptoms and signs yielded a sensitivity of 51%, specificity of 83%, positive likelihood ratio of 3.2, and negative likelihood ratio of 0.5 for acute HIV-1 infection. The recognition of primary HIV-1-infection illness in high-risk populations and subsequent risk-reduction counseling could potentially reduce secondary HIV-1 transmission during this highly infectious period.

Genital shedding of herpes simplex virus (HSV) results in frequent transmission of infection to sexual partners and neonates. In a cross-sectional study, cervical shedding of HSV DNA was detected in 43 (17%) cervical swab samples from 273 women seropositive for HSV-1, HSV-2, and human immunodeficiency virus type 1 (HIV-1). Cervical shedding of HSV was significantly associated with oral contraception (adjusted odds ratio [aOR], 4.5; 95% confidence interval [CI], 1.7-12.2), use of depo-medroxyprogesterone acetate (aOR, 3.2; 95% CI, 1.3-7.7), and pregnancy (aOR, 7.9; 95% CI, 2.0-31.7). In the subgroup of women who were not pregnant and not using hormonal contraception (n = 178), serum vitamin A was highly predictive of cervical HSV shedding: concentrations indicating severe deficiency, moderate deficiency, low-normal, and high-normal status were associated with 29%, 18%, 8%, and 2% prevalences of cervical HSV shedding, respectively (linear trend, P = .0002). Several factors appear to influence HSV reactivation in HIV-1 seropositive women.

OBJECTIVE: To evaluate whether resistance to HIV-1 infection in a subset of highly exposed sex workers correlates with resistance at the cellular level.DESIGN: In vitro evaluation of susceptibility to infection by Kenyan HIV-1 isolates and cellular production of potential mediators of resistance.SETTING: Samples were collected in a primary care clinic in Nairobi.PATIENTS: Thirteen individuals from a cohort of sex workers with a similar risk of acquiring HIV infection and six unexposed controls.INTERVENTIONS: Subjects were provided with appropriate primary care and counselling on the prevention of sexually transmitted diseases.RESULTS: No inherent cellular resistance to infection was identified. CD8+cells from a subset of subjects strongly inhibited viral replication.CONCLUSIONS: Lack of infection in this cohort was not attributable to factors inherent to CD4+cells. Resistance to HIV infection is likely to be multifactorial, and products of CD8+cells and unique features of mucosal sites probably contribute to this state.

A prospective cohort study was conducted to examine the relationship between vaginal colonization with lactobacilli, bacterial vaginosis (BV), and acquisition of human immunodeficiency virus type 1 (HIV-1) and sexually transmitted diseases in a population of sex workers in Mombasa, Kenya. In total, 657 HIV-1-seronegative women were enrolled and followed at monthly intervals. At baseline, only 26% of women were colonized with Lactobacillus species. During follow-up, absence of vaginal lactobacilli on culture was associated with an increased risk of acquiring HIV-1 infection (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.2-3.5) and gonorrhea (HR, 1.7; 95% CI, 1.1-2.6), after controlling for other identified risk factors in separate multivariate models. Presence of abnormal vaginal flora on Gram's stain was associated with increased risk of both HIV-1 acquisition (HR, 1.9; 95% CI, 1.1-3.1) and Trichomonas infection (HR, 1.8; 95% CI, 1.3-2.4). Treatment of BV and promotion of vaginal colonization with lactobacilli should be evaluated as potential interventions to reduce a woman's risk of acquiring HIV-1, gonorrhea, and trichomoniasis.

Cervical shedding of cytomegalovirus (CMV) is important in transmission of CMV to exposed sexual partners and neonates. We evaluated prevalence and correlates of CMV DNA shedding in cervical secretions from a large cohort of HIV-1-seropositive women. Using polymerase chain reaction (PCR) assays, CMV DNA was detected in 183 (59%) cervical swab samples from 311 women. Cervical shedding of CMV DNA was significantly associated with shedding of HIV-1 DNA (odds ratio 1.8; 95% confidence interval 1.1-2.8). CMV shedding was also more frequent in women with Neisseria gonorrhoeae and Trichomonas vaginalis infections, but these associations were not statistically significant. Cervical shedding of CMV in HIV-1-infected women is very frequent and may reflect higher risk of transmission to sexual partners and neonates than previously appreciated.

In sub-Saharan Africa, where the effects of human immunodeficiency virus type 1 (HIV-1) have been most devastating, there are multiple subtypes of this virus. The distribution of different subtypes within African populations is generally not linked to particular risk behaviors. Thus, Africa is an ideal setting in which to examine the diversity and mixing of viruses from different subtypes on a population basis. In this setting, it is also possible to address whether infection with a particular subtype is associated with differences in disease stage. To address these questions, we analyzed the HIV-1 subtype, plasma viral loads, and CD4 lymphocyte levels in 320 women from Nairobi, Kenya. Subtype was determined by a combination of heteroduplex mobility assays and sequence analyses of envelope genes, using geographically diverse subtype reference sequences as well as envelope sequences of known subtype from Kenya. The distribution of subtypes in this population was as follows: subtype A, 225 (70.3%); subtype D, 65 (20.5%); subtype C, 22 (6.9%); and subtype G, 1 (0.3%). Intersubtype recombinant envelope genes were detected in 2.2% of the sequences analyzed. Given that the sequences analyzed represented only a small fraction of the proviral genome, this suggests that intersubtype recombinant viral genomes may be very common in Kenya and in other parts of Africa where there are multiple subtypes. The plasma viral RNA levels were highest in women infected with subtype C virus, and women infected with subtype C virus had significantly lower CD4 lymphocyte levels than women infected with the other subtypes. Together, these data suggest that women in Kenya who are infected with subtype C viruses are at more advanced stages of immunosuppression than women infected with subtype A or D. There are at least two models to explain the data from this cross-sectional study; one is that infection with subtype C is associated with a more rapid disease progression, and the second is that subtype C represents an older epidemic in Kenya. Discriminating between these possibilities in a longitudinal study will be important for increasing our understanding of the role of specific subtypes in the transmission and pathogenesis of HIV-1.

If human immunodeficiency virus type 1 (HIV-1) vaccines are to be highly effective, it is essential to understand the virologic factors that contribute to HIV-1 transmission. It is likely that transmission is determined, in part, by the genotype or phenotype (or both) of infectious virus present in the index case, which in turn will influence the quantity of virus that may be exchanged during sexual contact. Transmission may also depend on the fitness of the virus for replication in the exposed individual, which may be influenced by whether a virus encounters a target cell that is susceptible to infection by that specific variant. Of interest, our data suggest that the complexity of the virus that is transmitted may be different in female and male sexual exposures.

Objective Although non-ulcerative sexually transmitted diseases (STD) and bacterial vaginosis are implicated as cofactors in heterosexual HIV-1 transmission, the mechanisms have not been defined. Recent in vitro data suggest that interleukin (IL)-10 may increase susceptibility of macrophages to HIV-1 infection. Therefore, we performed this study to assess whether non-ulcerative STD are associated with detection of IL-10 in the female genital tract. Methods Women with clinical pelvic inflammatory disease with or without cervicovaginal discharge were recruited from an STD clinic in Nairobi, Kenya. Endocervical and endometrial specimens were obtained for Neisseria gonorrhoeae and Chlamydia trachomatis DNA detection, Trichonomas vaginalis culture, and CD4 and CD8 T-cell enumeration. Bacterial vaginosis was diagnosed by Gram stain. IL-10 was detected in endocervical specimens using enzyme-linked immunosorbent assay. Blood was obtained for HIV-1 serology. Results One hundred and seventy-two women were studied. N. gonorrhoeae, C. trachomatis, bacterial vaginosis, and T. vaginalis were detected in 38 (21%), 17 (9%), 71 (43%), and 22 (12%) women, respectively. Cervical IL-10 was detected more often in women with N. gonorrhoeae [adjusted odds ratio (AOR), 3.4; 95% confidence interval (CI), 1.4-8.4], C. trachomatis (AOR, 4.4; 95% CI, 1.2-15.6), and bacterial vaginosis (AOR, 3.1; 95% CI, 1.4-6.9) than in women without these infections. Conclusions The association of non-ulcerative STD and bacterial vaginosis with increased frequency of IL-10 detection in endocervical secretions suggests a potential mechanism through which these infections may alter susceptibility to HIV-1 infection in women.

Most HIV-1 transmission is sexual; therefore immune responses in the genital mucosa may be important in mediating protection against HIV infection. This study examined HIV-1-specific mucosal immunoglobulin A (IgA) in a cohort of HIV-1-resistant Kenyan female sex workers. HIV-1-specific immune responses were compared in HIV-1-resistant and HIV-1-infected sex workers and in lower risk uninfected women. Cervical and vaginal samples from each group were tested for HIV-1-specific IgA and IgG by enzyme immunoassay. Systemic T-helper lymphocyte cell responses to HIV-1 envelope peptide epitopes were assayed using an interleukin 2 bioassay. HIV-1 risk-taking behaviors were assessed using standardized questionnaires. HIV-1-specific IgA was present in the genital tract of 16 out of 21 (76%) HIV-1-resistant sex workers 5 out of 19 (26%) infected women and 3 out of 28 (11%) lower-risk women (P < 0.0001). Among lower risk women the presence of HIV-1-specific IgA was associated with HIV-1 risk- taking behavior. Systemic T-helper lymphocyte responses to HIV-1 envelope peptides were present in 11 out of 20 (55%) HIV-1- resistant women 4 out of 18 (22%) infected women and 1 out of 25 (4%) lower-risk women (P < 0.001). T-helper lymphocyte responses did not correlate with the presence of titer of virus-specific mucosal IgA in any study group. HIV-1-specific IgA is present in the genital tract of most HIV-1-resistant Kenyan sex workers and of a minority of lower risk uninfected women where it is associated with risk-taking behavior. These data suggest a role for mucosal HIV-1-specific IgA responses in HIV-1 resistance independent of host cellular responses. (authors)

To determine the effect of human immunodeficiency virus type 1 (HIV-1) infection upon pelvic inflammatory disease (PID), a laparoscopic study of acute PID was conducted in Nairobi, Kenya. Subjects underwent diagnostic laparoscopy, HIV-1 serology, and testing for sexually transmitted diseases. Of the 133 women with laparoscopically verified salpingitis, 52 (39%) were HIV-1-seropositive. Tubo-ovarian abscesses (TOA) were found in 33% of HIV-1-infected and 15% of HIV-1-uninfected women (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.2-6.5). Among seropositive women, TOA was found in 55% of those with CD4 cell percent14% vs. 28% with CD4 cell percent14% (OR 3.1, 95% CI 0.6-15.3). Neisseria gonorrhoeae was detected in 37 women (28%) and Chlamydia trachomatis in 12 (9%); neither was significantly related to HIV-1 seropositivity. Length of hospitalization was not affected by HIV-1 serostatus overall but was prolonged among HIV-1-infected women with CD4 cell percent14%. Among patients with acute salpingitis, likelihood of TOA was related to HIV-1 infection and advanced immunosuppression. In general, HIV-1-seropositive women with acute salpingitis responded well to treatment.

Major histocompatibility complex (MHC) gene products are expressed on human immunodeficiency virus (HIV)-infected cells and incorporated into the lipid envelope of HIV virions. Macaques immunized with human MHC gene products are protected from simian immunodeficiency virus challenge when the virus is grown in cells expressing the same MHC alleles. To relate these findings to mother-to-child transmission of HIV-1, investigations of whether sharing HLA between mother and infant influenced the risk of transmission of HIV-1 to the child were carried out. Class I HLA concordance was independently associated with a stepwise increase in the risk of perinatal HIV-1 transmission for each additional concordant allele (odds ratio, 2.63; 95% confidence interval, 1.36-5.07; P = .003). Thus, discordant HLA may provide infants with a means of protection against HIV-1 as a result of allogeneic infant anti-maternal MHC immune responses.

Searching for mechanisms of natural resistance to HIV infection with which to guide HIV vaccine design, we have examined antibody responses to HLA class I antigens in children of HIV-1-infected mothers. Anti-HLA antibodies are known to block HIV infectivity in vitro and can be protective against SIV challenge in macaques immunized with purified class I HLA. It was hypothesized that alloantibody to maternal HLA in children might contribute to the prevention of mother-to-child transmission of HIV-1. In fact, a surprisingly high proportion of the children examined, 22%, were found to have antibody against class I alloantigens. This alloantibody, however, did not correlate with the HIV status of the children and was found in a similar proportion of children of HIV-negative mothers. The HLA specificity of the antibody was not correlated with noninherited maternal HLA alleles and occurred with a higher frequency in older children. This result suggests environmental factors, rather than exposure to maternal cells, are involved in the formation of the alloantibody. The finding that anti-allo-class I HLA antibodies are not associated with a decreased risk of mother-to-child transmission indicates that this humoral immune response is unlikely to be the natural mechanism that accounts for the lack of transmission observed in many births. This result, however, does not preclude the further investigation of cellular alloimmune responses, or the use of alloimmunization as an artificial HIV immunization strategy.