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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106380-01A1
Application #
8603215
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Mehra, Vijay L
Project Start
2013-05-22
Project End
2018-04-30
Budget Start
2013-05-22
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$474,093
Indirect Cost
$172,123
Name
Duke University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Himes, Jonathon E; Goswami, Ria; Mangan, Riley J et al. (2018) Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys. Mucosal Immunol 11:1716-1726
Martinez, David R; Fouda, Genevieve G; Peng, Xinxia et al. (2018) Noncanonical placental Fc receptors: What is their role in modulating transplacental transfer of maternal IgG? PLoS Pathog 14:e1007161
Nguyen, Quang N; Martinez, David R; Himes, Jonathon E et al. (2018) Predominant envelope variable loop 2-specific and gp120-specific antibody-dependent cellular cytotoxicity antibody responses in acutely SIV-infected African green monkeys. Retrovirology 15:24
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; 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
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
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
Fouda, Genevieve G; Moody, M Anthony; Permar, Sallie R (2015) Antibodies for prevention of mother-to-child transmission of HIV-1. Curr Opin HIV AIDS 10:177-82
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

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