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.
|Fouda, Genevieve G; Eudailey, Joshua; Kunz, Erika L et al. (2017) Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization. Mucosal Immunol 10:228-237|
|Douglas, Ayooluwa O; Martinez, David R; Permar, Sallie R (2017) The Role of Maternal HIV Envelope-Specific Antibodies and Mother-to-Child Transmission Risk. Front Immunol 8:1091|
|Zhang, Ruijun; Alam, S Munir; Yu, Jae-Sung et al. (2016) Novel Monoclonal Antibodies for Studies of Human and Rhesus Macaque Secretory Component and Human J-Chain. Monoclon Antib Immunodiagn Immunother 35:217-26|
|Zhang, Ruijun; Martinez, David R; Nguyen, Quang N et al. (2016) Envelope-specific B-cell populations in African green monkeys chronically infected with simian immunodeficiency virus. Nat Commun 7:12131|
|Jeffries Jr, T L; Sacha, C R; Pollara, J et al. (2016) The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells. Mucosal Immunol 9:414-27|
|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|
|Pollara, Justin; McGuire, Erin; Fouda, Genevieve G et al. (2015) Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1. J Virol 89:9952-61|
|Richard, Jonathan; Veillette, Maxime; Brassard, Nathalie et al. (2015) CD4 mimetics sensitize HIV-1-infected cells to ADCC. Proc Natl Acad Sci U S A 112:E2687-94|
|Kelly, Matthew S; Benjamin, Daniel K; Puopolo, Karen M et al. (2015) Postnatal Cytomegalovirus Infection and the Risk for Bronchopulmonary Dysplasia. JAMA Pediatr 169:e153785|
|Shen, Xiaoying; Duffy, Ryan; Howington, Robert et al. (2015) Vaccine-Induced Linear Epitope-Specific Antibodies to Simian Immunodeficiency Virus SIVmac239 Envelope Are Distinct from Those Induced to the Human Immunodeficiency Virus Type 1 Envelope in Nonhuman Primates. J Virol 89:8643-50|
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