This proposal addresses a novel concept regarding the failure of cytotoxic T lymphocytes in the immunopathogenesis of HIV-1 infection. While scattered reports have suggested that there may be examples of epitope variation causing CTL "antagonism" or anergy, the phenomenon has been poorly understood and it has been impossible to determine the degree to which this process is sporadic or widespread. We present a novel hypothesis and build the case that HIV-1 epitope mutation causing anergy of responding CTLs may be a generalized process. Tapping into the growing understanding of anergy in general, we will explore the effect of anergy in CTL control of HIV-1.
Our specific aims are:
Aim 1 : To demonstrate epitope variants that induce anergy in HIV-1-specific CTLs. HIV-1-specific TCRs from infected persons will be used to generate phenotypically normal CTLs by transducing normal CD8+ T cells. These CTLs will be screened functionally against epitope variants from the same persons to identify anergy-inducing mutants, with confirmation using HIV-1-infected cells.
Aim 2 : To demonstrate the functional impact of anergy-inducing variants within HIV-1 in vivo. A humanized SCID mouse model with HIV-1-specific TCR-transduced CTLs will be tested for anergy induction by infection with HIV-1 containing epitope mutations.

Public Health Relevance

The cytotoxic T lymphocyte response is the best documented arm of immunity with a positive impact on the progression of disease in HIV-1 infection. Many promising therapies plan to harness this arm of immunity, but taking the limitations and mechanisms of failure of immunity will be crucial to success. This project explores a major limitation of cytotoxic T lymphocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110343-01A1
Application #
8738477
Study Section
Special Emphasis Panel (ZRG1-AARR-E (02))
Program Officer
Embry, Alan C
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$207,900
Indirect Cost
$72,900
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095