Differential Binding of IgG and IgA to Mucus of the Female Reproductive Tract

Fahrbach, Kelly M.; Malykhina, Olga; Stieh, Daniel J.; Hope, Thomas J.

doi:10.1371/journal.pone.0076176

Cited by 74 publications

(69 citation statements)

References 26 publications

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“…Whether IgG can also contribute to this inhibition is not entirely clear. Other mechanisms evoked include the possible hindrance of HIV mobility trapping of viruses linked to IgG and IgA within mucin layers outside the cervico-vaginal epithelium (125,126) and viral capture by sIgA and IgG.…”

Section: Plausible Nonneutralizing Antibody Mechanisms Of Protectionmentioning

confidence: 99%

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Excler¹,

Ake²,

Robb³

et al. 2014

Clin. Vaccine Immunol.

106

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Animal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nNAb) without neutralizing activity in vitro may play an important role in protection against viral infection in vivo. This was illustrated by the recent human immunodeficiency virus (HIV) RV144 vaccine efficacy trial, which demonstrated that HIV-specific IgG-mediated nNAb directed against the V2 loop of HIV type 1 envelope (Env) were inversely correlated with risk for HIV acquisition, while Env-specific plasma IgA-mediated antibodies were directly correlated with risk. However, tier 1 NAb in the subset of responders with a low level of plasma Env-specific IgA correlated with decreased risk. Nonhuman primate simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) challenge studies suggest that Env-mediated antibodies are essential and sufficient for protection. A comparison of immune responses generated in human efficacy trials reveals subtle differences in the fine specificities of the antibody responses, in particular in HIV-specific IgG subclasses. The underlying mechanisms that may have contributed to protection against HIV acquisition in humans, although not fully understood, are possibly mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other nonneutralizing humoral effector functions, such as antibody-mediated phagocytosis. The presence of such functional nNAb in mucosal tissues and cervico-vaginal and rectal secretions challenges the paradigm that NAb are the predominant immune response conferring protection, although this does not negate the desirability of evoking neutralizing antibodies through vaccination. Instead, NAb and nNAb should be looked upon as complementary or synergistic humoral effector functions. Several HIV vaccine clinical trials to study these antibody responses in various prime-boost modalities in the systemic and mucosal compartments are ongoing. The induction of high-frequency HIV-specific functional nNAb at high titers may represent an attractive hypothesis-testing strategy in future HIV vaccine efficacy trials. The identification of immune markers that correlate with protection against infection or disease after vaccination (or natural infection) remains the "holy grail" for vaccine scientists, as these immune markers have the potential to expedite vaccine development and provide unique insights into the pathogenesis of infection. For most of the vaccines available today, a functional antibody response is the identified correlate of protection (1). In the cases of candidate preventive human immunodeficiency virus (HIV) vaccines and experimental vaccines against the closely related retrovirus simian immunodeficiency virus (SIV), recent studies have suggested an antibody correlate of risk or protection. However, these studies suggested an association with antibodies that did not mediate broad or potent neutralization (2-5).Transmission of HIV type 1 (HIV-1) occurs through homosexual or heterosexual intercourse, through inje...

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Section: Plausible Nonneutralizing Antibody Mechanisms Of Protectionmentioning

confidence: 99%

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Excler¹,

Ake²,

Robb³

et al. 2014

Clin. Vaccine Immunol.

106

View full text Add to dashboard Cite

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“…While one recent study demonstrated that injectable DMPA was associated with both HIV acquisition and increased CCR5 expression on cervical CD4+ T cells [83], another actually showed a decrease in cervical CCR5+ CD4 cells after starting DMPA [84]. Furthermore, injectable progestins may have important influences on the amount and the physical characteristics of cervicovaginal mucus, which also constitutes an important barrier to HIV transmission [85,86], although no major impact on the vaginal microbiome has been seen to date [87].…”

Section: Biological Factors That May Enhance Hiv Transmission In Sub-mentioning

confidence: 99%

Inflammation and HIV Transmission in Sub-Saharan Africa

et al. 2015

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While the per-contact risk of sexual HIV transmission is relatively low, it is fourfold higher in sub-Saharan Africa, and this may partly explain the major global disparities that exist in HIV prevalence. Genital immune parameters are key determinants of HIV transmission risk, including epithelial integrity and the presence of highly HIV-susceptible intraepithelial or submucosal CD4+ T cell target cells. Biological parameters that may enhance mucosal HIV susceptibility in highly HIV-affected regions of sub-Saharan Africa include increased levels of mucosal inflammation, which can affect both epithelial integrity and target cell availability, as well as the increased mucosal surface area that is afforded by an intact foreskin, contraceptive choices, and intravaginal practices. There are multifactorial causes for increased mucosal inflammation, with the prevalence and nature of common co-infections being particularly relevant.

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“…[53][54][55] Recent studies have demonstrated interactions between FRT mucus and IgG and IgA, which would potentially trap and immobilize pathogens in the mucus and cleared as the mucus is shed. 52 Indeed, cervical-vaginal mucus has been shown to have an activity that hinders HIV-1 movement. 56 Radtke et al 57 showed that MUC 1, 4, and 16 were upregulated in 3D human ectocervical epithelial cell model upon stimulation with synthetic viral agonist Poly(I:C), indicating the dynamic nature of the MUC proteins in the FRT.…”

Section: Antimicrobials In Frt Secretionsmentioning

confidence: 99%

Secreted Mucosal Antimicrobials in the Female Reproductive Tract that are Important to Consider forHIVPrevention

Ghosh

2014

American J Rep Immunol

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The mucosal microenvironment of the female reproductive tract (FRT) is rich in secreted endogenous antimicrobials that provide the first line of defense against pathogens. This review focuses on the spectrum of secreted antimicrobials found in the FRT that have anti-HIV functions and are regulated by the natural hormonal changes in women's life cycle. Understanding the complex nature of FRT, mucosal microenvironment will enable us to better design therapeutic interventions for women against sexually transmitted pathogens.

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Differential Binding of IgG and IgA to Mucus of the Female Reproductive Tract

Cited by 74 publications

References 26 publications

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Inflammation and HIV Transmission in Sub-Saharan Africa

Secreted Mucosal Antimicrobials in the Female Reproductive Tract that are Important to Consider forHIVPrevention

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