A successful HIV-1 vaccine must elicit immune responses that impede virus transmission at mucosal sites of virus exposure. However, HIV-1 vaccine development is hampered by a lack of understanding of the epitope-specificity and functional role of HIV-1 Envelope (Env)-specific antibodies produced by mucosal B cell populations. The goal of this proposal is to determine the ability of naturally-elicited mucosal antibodies to block mucosal HIV-1 transmission. Breast milk is a rich source of mucosal antibodies which represent the ontogeny of the gastrointestinal B cell population (the "gut-mammary axis"). Moreover, these mucosal antibodies may contribute to passive protection against HIV-1 acquisition in the majority of HIV-1-exposed, breastfed infants. We recently established the technology required for isolation of HIV-1 Env-specific B cells and recombinant production of their monoclonal antibodies (mAbs) from colostrum of HIV-infected, lactating women. Using this technique, we isolated novel HIV-1 Env-specific mucosal IgG and IgA antibodies from breast milk B cells, and demonstrated their neutralizing and nonneutralizing functions. As mucosal B cell responses are compartmentalized from those in peripheral blood, we hypothesize that the repertoire of HIV-1 Env-specific-IgG/IgA antibodies isolated from mammary B cells are genetically and functionally distinct to those isolated from peripheral B cells. In this proposal, we will 1) contrast the genetc characteristics and epitope-specificity of HIV-1 Env-specific antibodies produced by systemic and mucosal B cells isolated from a repository of breast milk and peripheral blood mononuclear cells of HIV-1-infected women;2) identify qualities and epitope-specificities of mucosal HIV-1 Env-specific IgG and IgA antibodies that possess potent in vitro neutralizing and nonneutralizing functions that may block HIV-1 transmission;and 3) determine the ability of mucosally-produced HIV Env-specific IgG and IgA antibodies to protect against virus acquisition in vivo, using the neonatal rhesus monkey/oral simian-HIV (SHIV) transmission model. This work will set the standard for the type of mucosal antibody responses that an effective HIV-1 vaccine should target. Moreover, our work will define the mucosal HIV-1 Env-specific IgG and IgA antibody responses that can protect against HIV-1 transmission to infants via breastfeeding, establishing the maternal antibody responses required to eliminate postnatal HIV-1 transmission.
HIV-1 vaccination will require elicitation of immune responses that impede transmission at mucosal surfaces. However, the protective capabilities of HIV-1 Envelope- specific mucosal antibody responses are not well characterized, thereby hindering development of an HIV-1 vaccine that elicits effective mucosal antibody responses. In this study, we will investigate the genetic characteristics, specificity, and transmission-blocking potential of HIV-1 Envelope-specific monoclonal antibodies isolated from a unique source of mucosal B cells, breast milk of HIV-1 infected women. This work will elucidate the qualities and specificty of readily-inducible mucosal antibody responses that can inhibit mucosal HIV-1 transmission, namely infant HIV-1 transmission via breastfeeding.
|Sacha, C R; Vandergrift, N; Jeffries Jr, T L et al. (2015) Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women. Mucosal Immunol 8:316-26|