Human cytidine deaminases APOBEC3 (A3) proteins are potent host defenses against HIV. These antiviral proteins induce lethal modification of cytosines to uracils in newly synthesized minus-strand viral DNA, resulting in abortive viral infection. HIV must overcome these host cellular defenses for successful viral replication. HIV-1 encodes a protein, Vif, which suppresses the antiviral effects of A3 proteins by targeting them for degradation through the 26S proteasome. Vif hijacks cellular Cullin5 (Cul5), ElonginB, and ElonginC to form a viral E3 ubiquitin ligase that targets A3G for polyubiquitination and degradation. Thus, identification of novel strategies to preserve the antiviral functions of A3 is n exciting new target for antiretroviral therapy. In this application, we propose to capitalize our expertise in HIV-1 Vif/A3 system and our new understanding of the viral evasion mechanism to develop a rapid cell-based assay for the identification of small molecule inhibitors of Vif and to further optimize and adapt the system for application to high throughput molecular screening of large compound libraries to identify molecules that inhibit HIV-1 replication. The proposed research is based on our recent discovery that CBF? is a key and unique regulator of HIV-1 Vif function. This study is expected to provide us with critical information regarding the design and development of effective intervention strategies against HIV.

Public Health Relevance

The HIV-1 virion infectivity factor (Vif) is an essential regulatory protein required for HIV-1 replication in natural target cells such as CD4+ T-cells and macrophages which express innate antiviral human APOBEC3G (A3G) and related cytidine deaminases. We have identified a unique regulator of Vif. The overall goal of this project is to develop a rapid cell-based assay for the identification of small molecule inhibitors of Vif and to further optimize and adapt the system for application to high throughput molecular screening of large compound libraries to identify molecules that inhibit HIV-1 replication.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI102798-02
Application #
8713917
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Miller, Roger H
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218