Human immunodeficiency virus (HIV) infection is associated with a progressive loss of CD4 T cells leading to immunodeficiency and AIDS, and is accompanied by the emergence of numerous opportunistic infections. Oral mucosa is a primary site for secondary infections such as those caused by Epstein Barr Virus (EBV). EBV causes oral hairy leukoplakia (OHL) in immunosuppressed patients and has been shown to actively replicate in the epithelial cells from OHL lesions. In contrast, epithelial cells from patients who are not immunosuppressed do not show active viral infection. This would suggest that HIV infection associated changes in the epithelial microenvironment leads to the reactivation of EBV. Though the advent of anti-retroviral therapy (ART) has had a significant impact on controlling HIV infection and has led to a lower incidence of opportunistic infections, studies have shown that patients who use ART eventually fail to control HIV infection. This failure to control viremia is associated with the reemergence of opportunistic infections such as EBV associated OHL. ? ? The exact mechanisms and the factors that lead to active replication of EBV in oral epithelial cells during HIV infection and ART have not been elucidated. The overall objective of this proposal is to delineate the mechanisms of EBV reactivation in the oral mucosa during long-term ART by correlating changes in epithelial cell function and T cell responses with the reactivation of EBV. ? ? Rhesus macaques experimentally infected with simian immunodeficiency virus (SIV) and treated with anti-retroviral therapy (PMPA and FTC) will be used in this study.
Specific aim 1 will evaluate the effect of ART on host oral epithelial cellular factors and how changes in these factors correlate with reactivation of EBV, and Specific aim 2 will determine the effect of ART on EBV-specific T cell responses with the objective of correlating EBV reactivation with failure of EBV-specific T cell responses. These studies will provide valuable insights into the mechanisms of EBV pathogenesis during long-term ART and help identify novel therapeutic targets to control EBV infection in HIV infected subjects. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21DE018339-02S1
Application #
7681385
Study Section
Special Emphasis Panel (ZDE1-PZ (19))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2007-03-01
Project End
2011-11-30
Budget Start
2008-09-01
Budget End
2011-11-30
Support Year
2
Fiscal Year
2008
Total Cost
$254,518
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
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
Teran, Rommy; Mitre, Edward; Vaca, Maritza et al. (2011) Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response. Clin Immunol 138:299-310
Uchida, Naoya; Bonifacino, Aylin; Krouse, Allen E et al. (2011) Accelerated lymphocyte reconstitution and long-term recovery after transplantation of lentiviral-transduced rhesus CD34+ cells mobilized by G-CSF and plerixafor. Exp Hematol 39:795-805
Geisbert, Thomas W; Daddario-DiCaprio, Kathleen M; Hickey, Andrew C et al. (2010) Development of an acute and highly pathogenic nonhuman primate model of Nipah virus infection. PLoS One 5:e10690
Kader, M; Wang, X; Piatak, M et al. (2009) Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol 2:439-49
Kader, M; Bixler, S; Roederer, M et al. (2009) CD4 T cell subsets in the mucosa are CD28+Ki-67-HLA-DR-CD69+ but show differential infection based on alpha4beta7 receptor expression during acute SIV infection. J Med Primatol 38 Suppl 1:24-31
Eberly, Matthew D; Kader, Muhamuda; Hassan, Wail et al. (2009) Increased IL-15 production is associated with higher susceptibility of memory CD4 T cells to simian immunodeficiency virus during acute infection. J Immunol 182:1439-48

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