Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel

Archary, Derseree; Seaton, Kelly E.; Passmore, Jo‐Ann S.; Werner, Lise.; Deal, Aaron; Dunphy, Laura J.; Arnold, Kelly B.; Yates, Nicole L.; Lauffenburger, Douglas A.; Bergin, Philip; Liebenberg, Lenine J.; Samsunder, Natasha; Mureithi, Marianne; Altfeld, Marcus; Garrett, Nigel; Karim, Quarraisha Abdool; Karim, Salim S Abdool; Morris, Lynn; Tomaras, Georgia D.

doi:10.1038/mi.2015.145

Cited by 13 publications

(20 citation statements)

References 67 publications

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“…The first approach examined six different antibody effector functions with two cell types: Natural Killer Cells and Monocytes across four different vaccine studies. Confirming earlier reports, the analysis by LASSO (the least absolute shrinkage and selection operator) and PLSDA (partial least‐squares discriminant analysis) also identified that HIV‐1 envelope IgG3 uniquely distinguished the efficacious vaccine RV144 regimen from the non‐efficacious VAX003 vaccine regimen. In a correlation network analysis using non‐case– control samples, the antibody effector functions of antibody‐dependent cellular cytotoxicity (ADCC), antibody‐dependent cell‐mediated phagocytosis (ADCP), and antibody‐dependent complement deposition (ADCD) were tethered to Env IgG1 and IgG3 responses.…”

Section: Immunological Mechanisms Of Protectionsupporting

confidence: 80%

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

Tomaras¹,

Plotkin

2017

Immunological Reviews

100

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Summary Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate—thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine.

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Section: Immunological Mechanisms Of Protectionsupporting

confidence: 80%

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

Tomaras¹,

Plotkin

2017

Immunological Reviews

100

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“…Similar to our findings, a recent study using samples from the CAPRISA 004 microbicide trial to determine if topical antiretroviral usage had an impact on mucosal and systemic antibody responses found that HIV-specific IgA and IgG responses are increased in the genital tract of individuals who acquire HIV infection in the presence of tenofovir gel (27). Since all women were HIV-1 seronegative at the time of sample collection, our findings suggest that a local IgA-mediated immune response to HIV-1 may be elicited through sexual HIV-1 exposure without resulting in a systemic anti-HIV-1 IgG response.…”

Section: Discussionsupporting

confidence: 76%

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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“…Binding of mucosal antibodies to HIV-1 Env proteins were measured by a custom HIV-1 binding antibody multiplex assay as described [3,4,[60][61][62][63]. Env proteins used included gp41, gp120 (clade B BaL), gp140 (consensus M ConS), V1/V2 loop (clade B CaseA V1/V2), and resurfaced core (RSC) proteins revealing the CD4bs (RSC3, and mutants RSC3Δ371, RSC3G367R, RSC3Δ371P363N abolishing CD4bs antibody binding [64]).…”

Section: Hiv-1-specific Binding Antibody Assaymentioning

confidence: 99%

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses

et al. 2016

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Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.

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Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel

Cited by 13 publications

References 67 publications

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

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

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses

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