HIV infection is associated with massive loss of memory CD4 T cells in mucosal tissues such as the gastrointestinal and oral mucosa. These CD4 T cells not only serve as a pool of readily available target cells for propagating HIV infection but are also critical for the generation of anti-viral CD8 T cell responses against previously exposed and opportunistic pathogens. Limited information exists regarding the ability of mucosal vaccination to protect the CD4 T cell compartment in mucosal sites. Recent studies have demonstrated that systemic vaccination induced suboptimal mucosal immune responses that were associated with partial protection of the mucosal CD4 T cells. Given the highly compartmentalized nature of the mucosal immune system it is highly likely that mucosal vaccination can induce stronger immune responses in mucosal tissues than systemic vaccination. The overall objectives of this proposal are to evaluate mucosal vaccination strategies to induce potent immune responses in the mucosa. We hypothesize that mucosal vaccination can induce potent immune responses that can better protect the CD4 T cells in the mucosa after challenge, and this protection will correlate with better long-term outcome. We propose to test this hypothesis using the rhesus macaque model.
In Specific aim 1 we will determine if systemic prime/mucosal boost can significantly amplify mucosal immune responses better than systemic boosting.
In Specific aim 2 we will determine if alternate mucosal vaccination routes are better at inducing potent immune responses in the mucosa.
In Specific aim 3 we propose to vaccinate mucosally with adjuvants to determine if it can potentiate immune responses in the mucosa that better correlate with protection. Overall these studies will allow us to delineate the role of vaccine induced mucosal immunity in protecting the mucosa CD4 T cell compartment from infection leading to better long-term outcome.
HIV causes immunodeficiency very rapidly by killing the cells it infects. Protecting these cells from infection is critical to prevent the devastating effect of HIV infection and the onset of secondary infections. This project explores the role of mucosal vaccination in protecting cells from getting infected with HIV thereby leading to a better long-term survival outcome. The studies proposed here will aid in the development of an effective vaccine against HIV.
|George, Jeffy; Lewis, Mark G; Renne, Rolf et al. (2015) Suppression of transforming growth factor ? receptor 2 and Smad5 is associated with high levels of microRNA miR-155 in the oral mucosa during chronic simian immunodeficiency virus infection. J Virol 89:2972-8|
|Brown, Dallas; Mattapallil, Joseph J (2014) Gastrointestinal tract and the mucosal macrophage reservoir in HIV infection. Clin Vaccine Immunol 21:1469-73|
|Onabajo, Olusegun O; Mattapallil, Joseph J (2013) Expansion or depletion of T follicular helper cells during HIV infection: consequences for B cell responses. Curr HIV Res 11:595-600|
|Onabajo, Olusegun O; George, Jeffy; Lewis, Mark G et al. (2013) Rhesus macaque lymph node PD-1(hi)CD4+ T cells express high levels of CXCR5 and IL-21 and display a CCR7(lo)ICOS+Bcl6+ T-follicular helper (Tfh) cell phenotype. PLoS One 8:e59758|
|Bixler, Sandra L; Mattapallil, Joseph J (2013) Loss and dysregulation of Th17 cells during HIV infection. Clin Dev Immunol 2013:852418|
|Bixler, Sandra L; Sandler, Netanya G; Douek, Daniel C et al. (2013) Suppressed Th17 levels correlate with elevated PIAS3, SHP2, and SOCS3 expression in CD4 T cells during acute simian immunodeficiency virus infection. J Virol 87:7093-101|
|Moore, Andrew C; Bixler, Sandra L; Lewis, Mark G et al. (2012) Mucosal and peripheral Lin- HLA-DR+ CD11c/123- CD13+ CD14- mononuclear cells are preferentially infected during acute simian immunodeficiency virus infection. J Virol 86:1069-78|
|George, Jeffy; Cofano, Egidio Brocca; Lybarger, Elizabeth et al. (2011) Early short-term antiretroviral therapy is associated with a reduced prevalence of CD8(+)FoxP3(+) T cells in simian immunodeficiency virus-infected controller rhesus macaques. AIDS Res Hum Retroviruses 27:763-75|
|Mattapallil, Mary J; Silver, Phyllis B; Mattapallil, Joseph J et al. (2011) Uveitis-associated epitopes of retinal antigens are pathogenic in the humanized mouse model of uveitis and identify autoaggressive T cells. J Immunol 187:1977-85|
|Kean, Leslie S; Sen, Sharon; Onabajo, Olusegun et al. (2011) Significant mobilization of both conventional and regulatory T cells with AMD3100. Blood 118:6580-90|
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