Because the gastrointestinal mucosa is a critical early site of viral replication and CD4 T-cell depletion, as well as the largest lymphoid organ in the body, assessment of the adaptive immune mechanisms functioning in this tissue may provide important new insights relevant to our understanding of the host-pathogen relationship. Our studies during the prior funding cycle indicated that a robust, often polyfunctional CD8 T-cell response is mounted in gut mucosa during chronic HIV infection. In the next funding cycle, we will build upon prior studies to test three complementary hypotheses concerning the role of mucosal immunity in HIV pathogenesis. Our studies will focus on (1) Polyfunctional mucosal T-cells as an immune correlate of non-progression;(2) The effects of antiretroviral therapy (ART) on CD8 T-cell phenotype and function in the gut;and (3) The role of mucosal regulatory T-cells in shaping polyfunctional adaptive immune responses. These studies will be conducted on paired blood and mucosal samples from HIV+ subjects on and off ART, including a well-characterized group of HIV controllers, and healthy controls.
In Specific Aim 1, we will test the hypothesis that polyfunctional, HIV-specific CD8 T-cells in mucosal tissues are an immune correlate of non-progression. For the purposes of this study, we define polyfunctional T cells as those capable of secreting multiple cytokines/chemokines and releasing cytolytic granules upon in vitro stimulation. Our hypothesis predicts that mucosal T-cell responses in individuals characterized as Elite Controllers (EC, viral load <75) and Viremic Controllers (VC, viral load 75-2,000) are stronger, more functionally complex, and broader than in Non-Controllers (NC, viral load >10,000).
For Specific Aim 2, we will focus on Non-Controllers who are beginning ART. We will test the hypotheses that (a) the gut microenvironment drives virus-specific memory CD8+ T-cells to immune senescence due to high antigen load, CD4 T-cell depletion, and local expression of ligands for PD- 1;and (b) ART will lead to only partial CD4 restoration and reversal of immune senescence in the gut. Finally, for Specific Aim 3, we will test the hypothesis that regulatory T-cells are present in mucosal tissues of HIV-infected individuals, and that these cells act locally within mucosal tissues to suppress HIV-specific effector functions. Taken together, these studies should greatly advance our understanding of the HIV-host relationship in mucosal tissues during chronic infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057020-10
Application #
8210992
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2003-07-11
Project End
2013-05-31
Budget Start
2012-02-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$364,858
Indirect Cost
$93,440
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Hughes, Sean M; Ferre, April L; Yandura, Sarah E et al. (2018) Cryopreservation of human mucosal tissues. PLoS One 13:e0200653
Kiniry, Brenna E; Hunt, Peter W; Hecht, Frederick M et al. (2018) Differential Expression of CD8+ T Cell Cytotoxic Effector Molecules in Blood and Gastrointestinal Mucosa in HIV-1 Infection. J Immunol 200:1876-1888
Baggaley, Rebecca F; Owen, Branwen N; Silhol, Romain et al. (2018) Does per-act HIV-1 transmission risk through anal sex vary by gender? An updated systematic review and meta-analysis. Am J Reprod Immunol 80:e13039
Kiniry, Brenna E; Li, Shengbin; Ganesh, Anupama et al. (2018) Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection. Mucosal Immunol 11:909-920
Owen, Branwen N; Elmes, Jocelyn; Silhol, Romain et al. (2017) How common and frequent is heterosexual anal intercourse among South Africans? A systematic review and meta-analysis. J Int AIDS Soc 19:21162
Kiniry, B E; Ganesh, A; Critchfield, J W et al. (2017) Predominance of weakly cytotoxic, T-betLowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: implications for HIV infection. Mucosal Immunol 10:1008-1020
Gosselin, Annie; Wiche Salinas, Tomas Raul; Planas, Delphine et al. (2017) HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy. AIDS 31:35-48
Hughes, Sean M; Shu, Zhiquan; Levy, Claire N et al. (2016) Cryopreservation of Human Mucosal Leukocytes. PLoS One 11:e0156293
Serrano-Villar, Sergio; Sainz, Talia; Lee, Sulggi A et al. (2014) HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog 10:e1004078
Leeansyah, Edwin; Ganesh, Anupama; Quigley, Máire F et al. (2013) Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood 121:1124-35

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