HIV-1 Specific IgA Detected in Vaginal Secretions of HIV Uninfected Women Participating in a Microbicide Trial in Southern Africa Are Primarily Directed Toward gp120 and gp140 Specificities

Seaton, Kelly E.; Ballweber, Lamar; Lan, Audrey; Donathan, Michele.; Hughes, Sean M.; Vojtech, Lucia; Moody, M. Anthony; Liao, Hua‐Xin; Haynes, Barton F.; Galloway, Christine G.; Richardson, Barbra A.; Karim, Salim Safurdeen. Abdool; Dezzutti, Charlene S.; McElrath, M. Juliana; Tomaras, Georgia D.; Hladik, Florian

doi:10.1371/journal.pone.0101863

Cited by 31 publications

(34 citation statements)

References 61 publications

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“…Given the loss of CD4+ T cells, and specifically T follicular helper (Tfh) cells which induce class switching of B cells, during HIV infection, a potential mechanism underlying altered microbiome could be loss of IgA control in mucosa, but these mechanisms have not been clearly defined. Of interest, recent studies have demonstrated that there is a dual specificity of IgA for the microbiome and HIV [98**,99]. Thus, altered IgA responses in the presence of HIV infection could be an underlying mechanism of microbiome dysbiosis or lack of immune control of the microbiota.…”

Section: Microbial Dysbiosis In Immunity and Inflammationmentioning

confidence: 99%

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

Zevin

McKinnon

Burgener

et al. 2016

Current Opinion in HIV and AIDS

218

149

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Purpose of Review To describe the mechanisms and consequences of both microbial translocation and microbial dysbiosis in HIV infection. Recent Findings Microbes in HIV are likely playing a large role in contributing to HIV pathogenesis, morbidities and mortality. Two major disruptions to microbial systems in HIV infection include microbial translocation and microbiome dysbiosis. Microbial translocation occurs when the bacteria (or bacterial products) that should be in the lumen of the intestine translocate across the tight epithelial barrier into systemic circulation, where they contribute to inflammation and pathogenesis. This is associated with poorer health outcomes in HIV infected individuals. In addition, microbial populations in the GI tract are also altered after HIV infection, resulting in microbiome dysbiosis, which further exacerbates microbial translocation, epithelial barrier disruption, inflammation, and mucosal immune functioning. Summary Altered microbial regulation in HIV infection can lead to poor health outcomes, and understanding the mechanisms underlying microbial dysbiosis and translocation may result in novel pathways for therapeutic interventions.

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Section: Microbial Dysbiosis In Immunity and Inflammationmentioning

confidence: 99%

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

Zevin

McKinnon

Burgener

et al. 2016

Current Opinion in HIV and AIDS

218

149

View full text Add to dashboard Cite

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“…HIV-specific binding and neutralizing antibodies have been described in the genital tract of HIV-infected women [13-15], and in highly-exposed but persistently HIV seronegative (HEPS) women [16-18]. HIV-specific antibodies from lower genital tract secretions have been shown to be predominantly IgG rather than IgA, suggesting that transudation of systemic HIV-specific IgG antibodies contributes to IgG dominance at this mucosal surface [13, 19-21].…”

Section: Introductionmentioning

confidence: 99%

Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women

Mkhize

Durgiah

Ashley

et al. 2016

Aids

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Background Broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the HIV envelope glycoprotein have been identified in blood from HIV-1 infected women. We investigated whether antibodies in the genital tract from these women share similar epitope specificities and functional profiles as those in blood. Methods IgG and IgA antibodies were isolated from cervicovaginal lavages or Softcups from 13 HIV-infected women in the CAPRISA 002 cohort using Protein G and Peptide M respectively. Binding antibodies to envelope antigens were quantified by ELISA and binding antibody multiplex assay. Neutralizing antibody titers and epitope targets were measured using the TZM-bl assay with Env-pseudotyped wild-type and mutated viruses. Results HIV-specific IgG, but not IgA, was detected in genital secretions and the ratio of total IgG to HIV-specific IgG was similar to plasma. HIV-specific IgG reacted with multiple envelope antigens, including V1V2, gp120, gp140 and gp41. Two women had high plasma titers of HIV-specific IgG3 which was also detected in their genital tract samples. IgG from the genital tract had neutralizing activity against both Tier 1 and Tier 2 primary HIV-isolates. Antibodies targeting well-known glycan epitopes and the membrane proximal region of gp41 were detected in genital secretions, and matched specificities in plasma. Conclusions Women with HIV-specific plasma bNAbs have overlapping specificities in their genital secretions, indicating that these predominantly IgG isotype antibodies may transudate from blood to the genital tract. These data provide evidence that induction of systemic HIV-specific bNAbs can lead to antiviral immunity at the portal of entry.

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“…There is, however, no reason to believe that this underestimation would be unevenly distributed between the study groups. Even though the specificities of the IgA antibodies detected in the Partners PrEP Study participants are not yet known, previous studies have shown that mucosal HIV-1-neutralizing IgA antibodies were directed against HIV-1 gp120 and/or HIV-1 gp41 (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis

Lund

Broliden

Pyra

et al. 2016

J Virol

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Although nonhuman primate studies have shown that simian immunodeficiency virus/simian-human immunodeficiency virus (SIV/SHIV) exposure during preexposure prophylaxis (PrEP) with oral tenofovir can induce SIV immunity without productive infection, this has not been documented in humans. We evaluated cervicovaginal IgA in Partners PrEP Study participants using a subtype C primary isolate and found that women on PrEP had IgA with higher average human immunodeficiency virus type 1 (HIV-1)-neutralizing magnitude than women on placebo (33% versus 7%; P ‫؍‬ 0.008). Using a cutoff of >90% HIV-1 neutralization, 19% of women on-PrEP had HIV-1-neutralizing IgA compared to 0% of women on placebo (P ‫؍‬ 0.09). We also estimated HIV-1 exposure and found that the proportion of women with HIV-1-neutralizing IgA was associated with the level of HIV-1 exposure (P ‫؍‬ 0.04). Taken together, our data suggest that PrEP and high levels of exposure to HIV may each enhance mucosal HIV-1-specific humoral immune responses in sexually exposed but HIV-1-uninfected individuals. IMPORTANCE Although there is not yet an effective HIV-1 vaccine, PrEP for at-risk HIV-1-uninfected individuals is a highly efficacious intervention to prevent HIV-1 acquisition and is currently being recommended by the CDC and WHO for all individuals at high risk of HIV-1 acquisition.We previously demonstrated that PrEP use does not enhance peripheral blood HIV-1-specific T-cell responses in HIV-exposed individuals. Here, we evaluate for cervicovaginal HIV-neutralizing IgA responses in genital mucosal secretions of HIV-exposed women, which is likely a more relevant site than peripheral blood for observation of potentially protective immune events occurring in response to sexual HIV-1 exposure for various periods. Furthermore, we assess for host response in the context of longitudinal quantification of HIV-1 exposure. We report that HIV-neutralizing IgA is significantly correlated with higher HIV-1 exposure and, furthermore, that there are more women with HIV-1-neutralizing IgA in the on-PrEP group than in the placebo group. T he development of novel human immunodeficiency virus type 1 (HIV-1) prevention strategies that reduce HIV-1 susceptibility and impart long-term immune protection is a high priority. Four randomized, placebo-controlled clinical trials, conducted among diverse geographic and at-risk populations, have demonstrated that HIV-1-uninfected persons taking a daily oral antiretroviral as preexposure prophylaxis (PrEP)-either tenofovir (TDF) alone or coformulated with emtricitabine (TDF/FTC)-are at substantially reduced risk of HIV-1 acquisition (1-4). In recognition of this, WHO has recently recommended PrEP use for all individuals at substantial risk of HIV-1. Since PrEP will increasingly be used as part of standard care in the context of HIV-1 vaccine studies, it is essential to better understand the potential effects of PrEP on the host immune response to HIV-1.While the primary mechanism of protection afforded by PrEP is thought to be through...

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HIV-1 Specific IgA Detected in Vaginal Secretions of HIV Uninfected Women Participating in a Microbicide Trial in Southern Africa Are Primarily Directed Toward gp120 and gp140 Specificities

Cited by 31 publications

References 61 publications

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women

HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis

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