HIV transmission via breast milk remains a significant mode of infant HIV transmission in the developing world. Interestingly, the majority of infants remain protected from breast milk transmission despite repeated low-dose exposures to the virus, with postnatal transmission occurring in only 10% of HIV-exposed, breastfed infants. This low rate of transmission raises the possibility that HIV-specific immunity in breast milk may protect infants from HIV transmission. We hypothesize that the evolution of compartmentalized virus quasispecies in breast milk is driven by virus-specific, local breast milk immunity. Using the rhesus monkey/SIV model of HIV pathogenesis, we will characterize cellular and humoral virus-specific immune responses and virus co-evolution in breast milk during acute and chronic SIV-infection. We will then investigate whether vaccination with a potent T cell-based vaccine regimen can elicit virus-specific immunity in breast milk. Uninfected, lactating Mamu-A*01+ rhesus monkeys will be vaccinated with plasmid DNA expressing the SIV genes gag, pol, and env, and boosted with a recombinant adenovirus vector expressing SIV gag, pol, and env. Vaccine-elicited SIV-specific cellular and humoral immune responses in breast milk will be examined throughout the vaccination schedule. Mucosal and systemic routes of vaccination will be compared for their ability to induce SIV-specific immune responses in breast milk. Finally, Mamu-A*01-H chronically SIV-infected, lactating rhesus monkeys will be vaccinated with the DNA prime/adenovirus boost regimen by the route that best elicited SIV-specific immune responses in the breast milk of uninfected rhesus monkeys. SIV-specific immune responses and virus replication kinetics in breast milk and blood will be examined in the chronically SIV-infected, lactating rhesus monkeys to determine if vaccine-elicited immune responses can control virus replication in breast milk. These studies will define the impact of virus-specific immunity in breast milk on local virus replication, and will provide a framework for the design of a maternal vaccine as a potential intervention to decrease breast milk transmission of HIV.
As breast milk transmission accounts for nearly one half of the 800,000 infant HIV infections occurring annually, interventions to impede transmission of HIV via breastfeeding are critical. Using the nonhuman primate model of HIV/AIDS, we will determine whether vaccination of lactating mothers can induce virus- specific immune responses in breast milk and reduce breast milk virus load.
|Fouda, G G; Eudailey, J; Kunz, E L et al. (2016) Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization. Mucosal Immunol :|
|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|
|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|
|Fouda, Genevieve G; Jaeger, Frederick H; Amos, Joshua D et al. (2013) Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk. Proc Natl Acad Sci U S A 110:18220-5|
|Fouda, Genevieve G A; Amos, Joshua D; Wilks, Andrew B et al. (2013) Mucosal immunization of lactating female rhesus monkeys with a transmitted/founder HIV-1 envelope induces strong Env-specific IgA antibody responses in breast milk. J Virol 87:6986-99|
|Ho, Carrie; Wu, Steven; Amos, Joshua D et al. (2013) Transient compartmentalization of simian immunodeficiency virus variants in the breast milk of african green monkeys. J Virol 87:11292-9|
|Friedman, James; Alam, S Munir; Shen, Xiaoying et al. (2012) Isolation of HIV-1-neutralizing mucosal monoclonal antibodies from human colostrum. PLoS One 7:e37648|
|Schmitz, Joern E; Ma, Zhong-Min; Hagan, Emily A et al. (2012) Memory CD4(+) T lymphocytes in the gastrointestinal tract are a major source of cell-associated simian immunodeficiency virus in chronic nonpathogenic infection of African green monkeys. J Virol 86:11380-5|
|Handley, Scott A; Thackray, Larissa B; Zhao, Guoyan et al. (2012) Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell 151:253-66|
|Mahlokozera, Tatenda; Kang, Helen H; Goonetilleke, Nilu et al. (2011) The magnitude and kinetics of the mucosal HIV-specific CD8+ T lymphocyte response and virus RNA load in breast milk. PLoS One 6:e23735|
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