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.
HIV-1-specific IgA has been described in the genital tract and plasma of HIV-1 highly exposed, persistently seronegative (HEPS) individuals, and IgA from these sites has been shown to neutralize ...HIV-1. This study examines the ability of IgA isolated from HEPS individuals to inhibit transcytosis across a tight epithelial cell layer. A Transwell system was established to model HIV-1 infection across the human mucosal epithelium. The apical-basolateral transcytosis of primary HIV-1 isolates across this mucosal model was examined in the presence and the absence of IgA isolated from the genital tract, saliva, and plasma of HEPS individuals enrolled in both a sex worker cohort in Nairobi, Kenya, and a discordant couple cohort in Italy. In the absence of IgA, HIV-1 primary isolates were actively transported across the epithelial membrane and were released on the opposite side of the barrier. These transcytosed HIV-1 particles retained their ability to infect human mononuclear cells. However, IgA purified from the mucosa and plasma of HEPS individuals was able to inhibit HIV-1 transcytosis. Inhibition was seen in three of six cervicovaginal fluid samples, five of 10 saliva samples, and three of six plasma samples against at least one of the two primary HIV-1 isolates tested. IgA from low risk, healthy control subjects had no inhibitory effect on HIV-1 transcytosis. The ability of mucosal and plasma IgA to inhibit HIV-1 transcytosis across the mucosal epithelium may represent an important mechanism for protection against the sexual acquisition of HIV-1 infection in HEPS individuals.
CONTEXT Sexually transmitted infections (STIs) are common in female sex workers
(FSWs) and may enhance susceptibility to infection with human immunodeficiency
virus type 1 (HIV-1). OBJECTIVE To ...examine regular antibiotic prophylaxis in FSWs as a strategy for
reducing the incidence of bacterial STIs and HIV-1. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial conducted between
1998-2002 among FSWs in an urban slum area of Nairobi, Kenya. Of 890 FSWs
screened, 466 who were seronegative for HIV-1 infection were enrolled and
randomly assigned to receive azithromycin (n = 230) or placebo (n = 236).
Groups were well matched at baseline for sexual risk taking and STI rates. INTERVENTION Monthly oral administration of 1 g of azithromycin or identical placebo,
as directly observed therapy. All participants were provided with free condoms,
risk-reduction counseling, and STI case management. MAIN OUTCOME MEASURES The primary study end point was incidence of HIV-1 infection. Secondary
end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus
ducreyi, as well as bacterial vaginosis. Analysis
of herpes simplex virus type 2 (HSV-2) infection was performed post hoc. RESULTS Seventy-three percent of participants (n = 341) were followed up for
2 or more years or until they reached an administrative trial end point. Incidence
of HIV-1 did not differ between treatment and placebo groups (4% 19 cases
per 473 person-years of follow-up vs 3.2% 16 cases per 495 person-years
of follow-up rate ratio RR, 1.2; 95% CI, 0.6-2.5). Incident HIV-1 infection
was associated with preceding infection with N gonorrhoeae (rate ratio RR, 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9). There was a reduced incidence in the treatment
group of infection with N gonorrhoeae (RR, 0.46;
95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95%
CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI,
0.40-0.78). The seroprevalence of HSV-2 infection at enrollment was 72.7%,
and HSV-2 infection at baseline was independently associated with HIV-1 acquisition
(RR, 6.3; 95% CI, 1.5-27.1). CONCLUSIONS Despite an association between bacterial STIs and acquisition of HIV-1
infection, the addition of monthly azithromycin prophylaxis to established
HIV-1 risk reduction strategies substantially reduced the incidence of STIs
but did not reduce the incidence of HIV-1. Prevalent HSV-2 infection may have
been an important cofactor in acquisition of HIV-1.
Understanding how individuals with a high degree of HIV exposure avoid persistent infection is paramount to HIV vaccine design. Evidence suggests that mucosal immunity, particularly virus-specific ...CTL, could be critically important in protection against sexually acquired HIV infection. Therefore, we have looked for the presence of HIV-specific CD8+ T cells in cervical mononuclear cells from a subgroup of highly HIV-exposed but persistently seronegative female sex workers in Nairobi. An enzyme-linked immunospot assay was used to measure IFN-gamma release in response to known class I HLA-restricted CTL epitope peptides using effector cells from the blood and cervix of HIV-1-resistant and -infected sex workers and from lower-risk uninfected controls. Eleven of 16 resistant sex workers had HIV-specific CD8+ T cells in the cervix, and a similar number had detectable responses in blood. Where both blood and cervical responses were detected in the same individual, the specificity of the responses was similar. Neither cervical nor blood responses were detected in lower-risk control donors. HIV-specific CD8+ T cell frequencies in the cervix of HIV-resistant sex workers were slightly higher than in blood, while in HIV-infected donor cervical response frequencies were markedly lower than blood, so that there was relative enrichment of cervical responses in HIV-resistant compared with HIV-infected donors. HIV-specific CD8+ T cell responses in the absence of detectable HIV infection in the genital mucosa of HIV-1-resistant sex workers may be playing an important part in protective immunity against heterosexual HIV-1 transmission.
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).
A randomized trial of monthly antibiotic prophylaxis to prevent sexually transmitted disease/HIV infection was performed from 1998 to 2002 in HIV-uninfected Kenyan FSWs. After the completion of trial, FSWs who had acquired HIV (cases) were matched 1: 4 with persistently uninfected controls based on study arm, duration of HIV-seronegative follow-up, and time of cohort enrolment. Blinded investigators assayed the ability at enrolment of genital IgA to neutralize primary HIV isolates as well as systemic HIV-specific cellular IFNgamma-modified enzyme-linked immunospot and proliferative responses.
The study cohort comprised 113 FSWs: 24 cases who acquired HIV and 89 matched controls. Genital HIV-neutralizing IgA was associated with reduced HIV acquisition (P = 0.003), as was HIV-specific proliferation (P = 0.002), and these associations were additive. HIV-specific IFNgamma production did not differ between case and control groups. In multivariable analysis, HIV-neutralizing IgA and HIV-specific proliferation each remained independently associated with lack of HIV acquisition. Genital herpes (HSV2) was associated with increased HIV risk and with reduced detection of HIV-neutralizing IgA.
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.
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.
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.
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 12–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.
We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1.
HLA-B*57 is associated with slower disease progression to AIDS, and CD8+ T cell responses to B*57-restricted epitopes are thought to contribute to this protective effect. In this study, we evaluate ...the B*57-restricted p24 KAFSPEVIPMF (KF11) immune response which is immunodominant during chronic infection. Previously, we observed that the KF11 clade variants KGFNPEVIPMF A2G,S4N and KAFNPEIIMPF S4N,V7I, sharing a position 4 mutation, are differentially recognized by KF11-specific T cells. By combining structural and cellular studies, we now demonstrate that the KF11 and A2G,S4N epitopes induce distinct functional responses in A2G,S4N and KF11-specific T cells, respectively, despite minimal structural differences between the individual B*57-peptide complexes. Recently, we also elucidated the highly distinct structure of KF11 in complex with B*5703, and have now characterized the CD8+ T cell repertoire recognizing this epitope. We now report striking features of TCR conservation both in terms of TCR Valpha and Vbeta chain usage, and throughout the hypervariable region. Collectively, our findings highlight unusual features of the B*5701/B*5703-KF11-specific immune responses which could influence disease progression and that might be important to consider when designing future vaccine regimens.
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.
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.
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.
Mucosal and plasma IgA from HEPS individuals can neutralize HIV-1 infection.
1 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford OX3 9DS, UK
2 University of St Andrews, School of Biology, St Andrews, UK
3 Nuffield Department of ...Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
4 International AIDS Vaccine Initiative, 110 William Street, New York, NY 10038, USA
5 Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
Correspondence Tomá Hanke tomas.hanke{at}imm.ox.ac.uk
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 primeboost 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 primeMVA 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.
Present address: Wellcome Trust Kilifi Labs, PO Box 230, Kilifi, Kenya.
To determine whether CD8 T lymphocytes from HIV-1-infected patients expressing B*5701 and B*5703 show broad cross-reactivity against different variants of a conserved p24 epitope, which might account ...for the good prognosis of HIV-1-infected individuals with HLA-B*57.
B*5701+ and B*5703+ were recruited from Nairobi, Kenya and from Oxford, UK. All patients had been HIV positive for at least 8 years and could be categorized as slow progressors.
CD8 cytotoxic T cell clones were generated from B*5701+ and B*5703+ donors and tested for their ability to recognize clade variants of an index p24 epitope in standard cytolytic assays. Cross-reactive responses in freshly isolated peripheral blood mononuclear cells (PBMC) were assessed by interferon-gamma (IFNgamma) production and tetramer binding.
Broad cross-clade reactivity for both cytolysis and tetramer binding was observed in CD8 T cell clones from patients harbouring the index epitope sequence. Patterns of cross-reactivity were similar in freshly isolated PBMC but varied between individuals in terms of strength and breath of responses generated. One common variant induced an unusual response with tetramer binding but often failed to induce IFNgamma production, and another was a weak stimulator of both IFNgamma and cytolytic activity.
B*5701+ and B5703+ donors demonstrate broad functional cross-reactivity to both common and rare variants of a dominant p24 epitope, which could be relevant to the association of B*57 alleles with slow progression to AIDS.
PDF
