Gut associated lymphoid tissue (GALT) harbors the majority of lymphoid tissue in the body and is an important site for viral replication and severe depletion of memory CD4+ T cells in human immunodeficiency virus-1 (HIV) infection. Patients on HAART display incomplete viral suppression and significantly slower restoration of CD4+ T cells in GALT than in peripheral blood and this correlates with persistent immune activation. The mechanisms contributing to chronic immune activation and HIV persistence in GALT during therapy have not been fully defined. The overall objective of this revised competitive renewal application is to determine the mechanisms of enteropathogenesis that contribute to chronic immune activation and viral persistence in GALT of HIV infected patients during HAART. We hypothesize that chronic immune activation in GALT is due to impaired gut epithelium renewal, loss of specific CD4+ T cell subsets, and residual viral replication in HIV infected patients during HAART. There are 3 specific aims: In HIV infected patients with or without HAART, we will (1) determine HIV replication dynamics and viral genomic diversity in GALT compared to peripheral blood. (2) investigate the molecular mechanisms of impaired renewal of the intestinal epithelial barrier and defects in cell maturation/differentiation along the villus-crypt axis. (3) investigate the prevalence, immunophenotype, and function of Th17 CD4+ T cells, a critical component of mucosal immune defense. The proposal capitalizes on our experience in enteropathogenic studies of HIV infection, our success in enrollment and longitudinal gut mucosal studies in patients, expertise in mucosal immunology, multicolor flow cytometry, gene expression analysis, and molecular virology, as well as the expertise of our collaborators in HIV genomic analysis and HIV patient care. The proposed studies will provide insights into the mechanisms that link chronic immune activation to impaired restoration of the gut mucosal immune system and viral persistence in HIV infection. Findings from these studies will be valuable in the elucidation of novel correlates of protection against HIV disease and may impact the development of improved vaccine and therapeutic approaches.

Public Health Relevance

Despite therapy, human immunodeficiency virus (HIV) is not completely eliminated from the body. We will examine the role of intestinal tissue in the persistence of HIV infection. Since the intestinal tissues contain most of the body's immune cells, persistent HIV infection leads to severe impairment of both digestive and immune function and may increase the rate of progression to AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061297-09
Application #
8208145
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Hamilton, Frank A
Project Start
2001-10-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2012
Total Cost
$359,931
Indirect Cost
$118,075
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
Jiang, Guochun; Santos Rocha, Clarissa; Hirao, Lauren A et al. (2017) HIV Exploits Antiviral Host Innate GCN2-ATF4 Signaling for Establishing Viral Replication Early in Infection. MBio 8:
Kis, Olena; Sankaran-Walters, Sumathi; Hoque, M Tozammel et al. (2016) HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition. Antimicrob Agents Chemother 60:2771-81
Glavan, T W; Gaulke, C A; Santos Rocha, C et al. (2016) Gut immune dysfunction through impaired innate pattern recognition receptor expression and gut microbiota dysbiosis in chronic SIV infection. Mucosal Immunol 9:677-88
Jiang, Guochun; Dandekar, Satya (2015) Targeting NF-?B signaling with protein kinase C agonists as an emerging strategy for combating HIV latency. AIDS Res Hum Retroviruses 31:4-12
Jiang, Guochun; Mendes, Erica A; Kaiser, Philipp et al. (2015) Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation. PLoS Pathog 11:e1005066
Jiang, Guochun; Mendes, Erica A; Kaiser, Philipp et al. (2014) Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase C?-NF-?B signaling. AIDS 28:1555-66
Nagy, Lauren H; Grishina, Irina; Macal, Monica et al. (2013) Chronic HIV infection enhances the responsiveness of antigen presenting cells to commensal Lactobacillus. PLoS One 8:e72789
Sena, Angela; Grishina, Irina; Thai, Anne et al. (2013) Dysregulation of anti-inflammatory annexin A1 expression in progressive Crohns Disease. PLoS One 8:e76969
Lerner, Paula; Guadalupe, Moraima; Donovan, Richard et al. (2011) The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy. J Virol 85:4772-82
Shen, Ruizhong; Meng, Gang; Ochsenbauer, Christina et al. (2011) Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages. PLoS Pathog 7:e1002060

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