Abstract

There is growing evidence that the host genetic make-up of an individual is a strong determinant of HIV/AIDS susceptibility. We have integrated genetics, immunology, and evolution, and used them as powerful tools to (a) uncover complex host gene-gene interactions that influence HIV-1 pathogenesis in vivo; (b) determine the relative contribution to these determinants to the HIV-1 epidemic at the population level;(c) translate these findings to real life practical issues such as improved clinical care of patients via geneticbased prognostication of AIDS as well as design and evaluation of vaccine trials;and (d) shed light on the immune correlates of a protective anti-HIV response in vivo that can be modeled for rational vaccine design. In the current application we will test the overall hypothesis that (I) expression of members of the CD4 - CD4 ligand - CCR5 - CCR5 ligand nexus, including relevant transducers of coreceptor signals, will alter HIV/AIDS susceptibility (aim #1);(II) expression of candidate genes that influence T cell dynamics and regulation will alter HIV/AIDS susceptibility (aim #2);and (III) HIV/AIDS susceptibility is linked to the gene dose of alpha-defensins (aim #3).
In aim #4, we will explore means to place host genetics in a broader framework, and will determine their influence on AIDS prognostication, T cell dynamics and other public health aspects of the epidemic. Thus, this proposal seeks funds to support a collaborative study to explore the genetic mechanisms underlying HIV/AIDS susceptibility by amalgamating the unique skills and resources of two different research teams, namely genetics (UTHSCSA), epidemiology/virology/statistics (WHMC), population genetics (Utah) and immunolog/virology (Vanderbilt). This study will utilize pre-existing, anonymous, unlinked human specimens. IRB approval for genetic study of these specimens has been previously obtained under expedited review authorized by 45 CFR 46.110, and is a continuation of an existing approved IRB proposal.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI046326-15
Application #
8619576
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sharma, Opendra K
Project Start
1999-07-16
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$666,363
Indirect Cost
$214,465

  Institution

Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229

  Publications

Huik, Kristi; Avi, Radko; Pauskar, Merit et al. (2016) A CCL5 Haplotype Is Associated with Low Seropositivity Rate of HCV Infection in People Who Inject Drugs. PLoS One 11:e0156850
Gornalusse, German G; Mummidi, Srinivas; Gaitan, Alvaro A et al. (2015) Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor. Proc Natl Acad Sci U S A 112:E4762-71
Okulicz, Jason F; Le, Tuan D; Agan, Brian K et al. (2015) Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals. JAMA Intern Med 175:88-99
Huik, Kristi; Avi, Radko; Uibopuu, Helen et al. (2014) Association between HIV-1 tropism and CCR5 human haplotype E in a Caucasian population. J Acquir Immune Defic Syndr 66:239-44
Huik, Kristi; Avi, Radko; Carrillo, Andrew et al. (2013) CCR5 haplotypes influence HCV serostatus in Caucasian intravenous drug users. PLoS One 8:e70561
Le, Tuan; Wright, Edwina J; Smith, Davey M et al. (2013) Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med 368:218-30
Kulkarni, Hemant; Okulicz, Jason F; Grandits, Greg et al. (2011) Early postseroconversion CD4 cell counts independently predict CD4 cell count recovery in HIV-1-postive subjects receiving antiretroviral therapy. J Acquir Immune Defic Syndr 57:387-95
Marconi, Vincent C; Grandits, Greg; Okulicz, Jason F et al. (2011) Cumulative viral load and virologic decay patterns after antiretroviral therapy in HIV-infected subjects influence CD4 recovery and AIDS. PLoS One 6:e17956
Catano, Gabriel; Chykarenko, Zoya A; Mangano, Andrea et al. (2011) Concordance of CCR5 genotypes that influence cell-mediated immunity and HIV-1 disease progression rates. J Infect Dis 203:263-72
Mamtani, Manju; Mummidi, Srinivas; Ramsuran, Veron et al. (2011) Influence of variations in CCL3L1 and CCR5 on tuberculosis in a northwestern Colombian population. J Infect Dis 203:1590-4

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