Hirbod T, Kaul R, Reichard C, Kimani J, Ngugi E, Bwayo JJ, et al. HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers

Infectious Diseases Unit, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden.
AIDS (London, England) (Impact Factor: 5.55). 04/2008; 22(6):727-35. DOI: 10.1097/QAD.0b013e3282f56b64
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Taha Hirbod, Jan 12, 2015
25 Reads
  • Source
    • "These include elevated CC-chemokines and bPRP2 within the saliva of HESN MSM [11], [12]. As well, HIV-neutralizing salivary IgA has been correlated with HIV protection in resistant individuals, and the potent antiviral activity of IgA has made it an attractive vaccine target [13]–[15]. Mucosal immune proteins within the rectum, including potential anti-HIV factors, have yet to be comprehensively described as they have been at other sites of HIV exposure (Table 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Sexual transmission of HIV occurs across a mucosal surface, which contains many soluble immune factors important for HIV immunity. Although the composition of mucosal fluids in the vaginal and oral compartments has been studied extensively, the knowledge of the expression of these factors in the rectal mucosa has been understudied and is very limited. This has particular relevance given that the highest rates of HIV acquisition occur via the rectal tract. To further our understanding of rectal mucosa, this study uses a proteomics approach to characterize immune factor components of rectal fluid, using saliva as a comparison, and evaluates its antiviral activity against HIV. Methods Paired salivary fluid (n = 10) and rectal lavage fluid (n = 10) samples were collected from healthy, HIV seronegative individuals. Samples were analyzed by label-free tandem mass spectrometry to comprehensively identify and quantify mucosal immune protein abundance differences between saliva and rectal fluids. The HIV inhibitory capacity of these fluids was further assessed using a TZM-bl reporter cell line. Results Of the 315 proteins identified in rectal lavage fluid, 72 had known immune functions, many of which have described anti-HIV activity, including cathelicidin, serpins, cystatins and antileukoproteinase. The majority of immune factors were similarly expressed between fluids, with only 21 differentially abundant (p<0.05, multiple comparison corrected). Notably, rectal mucosa had a high abundance of mucosal immunoglobulins and antiproteases relative to saliva, Rectal lavage limited HIV infection by 40–50% in vitro (p<0.05), which is lower than the potent anti-HIV effect of oral mucosal fluid (70–80% inhibition, p<0.005). Conclusions This study reveals that rectal mucosa contains many innate immune factors important for host immunity to HIV and can limit viral replication in vitro. This indicates an important role for this fluid as the first line of defense against HIV.
    PLoS ONE 06/2014; 9(6):e100820. DOI:10.1371/journal.pone.0100820 · 3.23 Impact Factor
  • Source
    • "Therefore, the general opinion is that more basic science studies of HIV cell entry and mucosal immunology are required to boost the development of an efficacious vaccine [2], [3]. Perhaps induction of a mucosal secretory immunoglobulin A (IgA) antibodies together with a cytotoxic response in mucosal and systemic CD8+ T cells is what novel efforts should aim at [4], [5]. In addition, it may be possible to reinforce innate immune mechanisms to enhance mucosal protection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intraepithelial lymphocytes (IELs) bearing the γδ T-cell receptor are a unique intestinal subset whose function remains elusive. Here, we examine how they behave in AIDS and during various regimens of antiretroviral treatment in order to obtain mechanistic insight into their adaptive or innate functional in vivo properties. IELs were studied by multimarker two-colour immunofluorescence in situ staining. Consecutive duodenal biopsies were obtained from advanced infection-prone HIV(+) patients (n = 30). The systemic adaptive immune status was monitored by determining T-cell subsets and immunoglobulins in peripheral blood. The γδ IEL ratio (median 14.5%, range 1.5-56.3%) was significantly increased (p<0.02) compared with that in clinically healthy HIV(-) control subjects (n = 11, median 2.8%; range 0.3-38%), although the number of γδ IELs per mucosal length unit (U) only tended to be increased (4.0/U in HIV(+) versus 3.2/U in HIV(-) subjects). Notably, the total number of CD3(+) IELs was significantly reduced in AIDS (p<0.0001, 39.6/U in HIV(+) versus 86.4/U in HIV(-) subjects). Almost 100% of the γδ IELs were CD8(-) and they often expressed the Vδ1/Jδ1-encoded epitope (median 65.2%). HIV(+) patients on highly active antiretroviral therapy only tended to have a lower ratio of γδ IELs (median 12.8%) than those receiving no treatment (median 14.3%) or 1 nucleoside analogue (NA) (median 23.5%) or 2 NAs (median 13.0%). This minimal variation among therapy groups, contrasting the treatment response of systemic and local adaptive immunity, harmonizes with the novel idea derived from animal experiments that γδ T cells are largely innate cells in first-line microbial defence.
    PLoS ONE 01/2012; 7(1):e29066. DOI:10.1371/journal.pone.0029066 · 3.23 Impact Factor
  • Source
    • "This may be unrealistic if certain STIs interact with HIV in unique ways that are unrelated to the presence of symptoms. For example, HSV-2 may inhibit the production of HIVneutralizing IgA antibodies, which appear to protect against HIV acquisition (Hirbod et al. 2008). However, given the wide confidence intervals around the odds ratios estimated in published meta-analyses, and the sources of bias inherent in STI cofactor estimation (Korenromp et al. 2001), it is difficult to argue that there is significant heterogeneity between STIs in terms of their effect on percontact HIV transmission probabilities, after controlling for symptoms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To assess the extent to which sexually transmitted infections (STIs) have contributed to the spread of HIV in South Africa and to estimate the extent to which improvements in STI treatment have reduced HIV incidence. A mathematical model was used to simulate interactions between HIV and six other STIs (genital herpes, syphilis, chancroid, gonorrhoea, chlamydial infection and trichomoniasis) as well as bacterial vaginosis and vaginal candidiasis. The effects of STIs on HIV transmission probabilities were assumed to be consistent with meta-analytic reviews of observational studies, and the model was fitted to South African HIV prevalence data. The proportion of new HIV infections in adults that were attributable to curable STIs reduced from 39% (uncertainty range: 24-50%) in 1990 to 14% (8-18%) in 2010, while the proportion of new infections attributable to genital herpes increased. Syndromic management programmes are estimated to have reduced adult HIV incidence by 6.6% (3.3-10.3%) between 1994 and 2004, by which time syndromic management coverage was 52%. Had syndromic management been introduced in 1986, with immediate achievement of 100% coverage and a doubling of the rate of health seeking, HIV incidence would have reduced by 64% (36-82%) over the next decade, but had the same intervention been delayed until 2004, HIV incidence would have reduced by only 5.5% (2.8-9.0%). Sexually transmitted infections have contributed significantly to the spread of HIV in South Africa, but STI control efforts have had limited impact on HIV incidence because of their late introduction and suboptimal coverage.
    Tropical Medicine & International Health 10/2011; 17(2):161-8. DOI:10.1111/j.1365-3156.2011.02906.x · 2.33 Impact Factor
Show more