Human antiviral protein APOBEC3G induces extensive mutations and prevents the accumulation of HIV DNA rendering the virus non-infectious. To evade this host defense mechanism, HIV expresses the virion infectivity factor (Vif). Vif mimics the substrate receptor in a multi-component cellular ubiquitin ligase and recruits the ligase to polyubiquitinate APOBEC3G for proteasome-mediated degradation. Through direct interactions with APOBEC3G and the ubiquitin ligase components ElonginB/ElonginC and Cullin5, Vif enables HIV to escape a key element of the innate immune response. Our overall goal is to establish the structural principles by which HIV Vif sequesters APOBEC3G and to provide structural details of the interactions between Vif and host cellular proteins. We will determine the crystal structures of HIV Vif in complex with its various cellular binding partners as well as a complete complex of Vif/APOBEC3G/ubiquitin ligase. Specifically, we will examine the structures of complexes that contain i) the Vif-ElonginB/ElonginC, ii) the Vif-Cullin5, and iii) the Vif- APOBEC3G interactions. Structural information gained from these studies will provide an in-depth understanding of the mechanism by which HIV Vif hijacks the host ubiquitin ligase to circumvent the innate immune response from APOBEC3G. Further, the structural details will enable the rational design of Vif inhibitors that might lead to new therapeutic interventions for HIV infection.

Public Health Relevance

The proposed research aims to establish the structural principles by which the HIV protein, virion infectivity factor (Vif) hijacks a cellular protein degradation pathway to evade the innate immune response from a human antiviral protein, APOBEC3G. The structural details obtained will provide new insights to the pathogenesis of HIV and may provide new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33AI078831-05
Application #
8278483
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sharma, Opendra K
Project Start
2008-03-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$387,229
Indirect Cost
$153,254
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520