The HIV-1 capsid is an important determinant of viral replication. Early studies demonstrated the intrinsic importance of the capsid in mediating uncoating of the viral core. More recently, the capsid has emerged as an important mediator of virus-host interactions. Cyclophilin A (CypA) is an abundant cellular protein known to bind the N-terminal domain of the capsid protein. CypA can promote infection of some HIV-1 strains in certain cells, but it can also inhibit infection. Despite many years of research, we still do not understand these mechanisms. I hypothesize that CypA modulates HIV-1 infection by regulating the interaction of specific cellular proteins with the HIV-1 capsid. Indeed, we have observed that CypA can regulate the non-human primate capsid-binding restriction factor, TRIM5?. However, the mechanism of this activity is poorly understood. I will determine the ability of CypA to regulate capsid-binding restriction factors by i) elucidating the mechanism of CypA-dependent TRIM5? restriction and ii) determining the ability of CypA to alter the capsid interactome using comparative proteomics.

Public Health Relevance

Human Immunodeficiency Virus-1 (HIV-1) is a devastating human pathogen;the HIV-1 capsid protein is critical for the ability of the virus to cause disease. There are no HIV-1 drugs, currently available, which target the HIV-1 capsid protein. The proposed research will investigate how cellular proteins interact with the capsid, and inform our ability to develop capsid-targeting drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AI108481-01
Application #
8603170
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Adger-Johnson, Diane S
Project Start
2013-11-28
Project End
Budget Start
2013-11-28
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$26,834
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Henning, Matthew S; Dubose, Brittany N; Burse, Mallori J et al. (2014) In vivo functions of CPSF6 for HIV-1 as revealed by HIV-1 capsid evolution in HLA-B27-positive subjects. PLoS Pathog 10:e1003868