Retroviruses have devised a number of strategies to evade cellular mechanisms aimed at preventing retroviral infection. HIV-1 expressesVif, a protein that counteracts the antiviral activity of the cytidine deaminases APOBEC3G and APOBEC3F. The nucleotide composition of the HIV-1 genome suggests, however, that protection from host-mediated viral cDNA deamination may not be absolute. In preliminary studies, we showed that vif genes encoding proteins that fail to degrade APOBEC3G, APOBEC3F or both can be detected in vivo. The loss of Vif function was mapped to single nucleotide substitutions. These studies indicate that natural variation in Vif function may profoundly impact the extent and direction of viral sequence evolution within HIV-1 infected individuals. The experiments proposed herein will determine the extent to which host mechanisms aimed to prevent retroviral infection, in fact, contribute to viral diversification and pathogenesis. We will analyze the fitness of viruses expressing Vif proteins that are closely related but differ in their ability to neutralize APOBEC3G or APOBEC3F activities. We will also test if variation in Vif function may be beneficial for viral adaptation under certain circumstances (e.g., in the presence of antiretroviral drugs) by determining whether cytidine deamination by APOBEC3G or APOBEC3F selects for certain drug resistance mutations. The pattern of hypermutations associated with partial protection from cytidine deamination will be correlated to HIV fitness. Since APOBEC3 enzymes induce hypermutations in different dinucleotide contexts the understanding of how activity against one enzyme but not the other is maintained is relevant for viral evolution. We will conduct structure function studies to determine whether domains other than the Vif SOCS box motif are necessary and essential for Vif mediated specific neutralization of APOBEC3 enzymes. Finally, we will assess the impact of reverse transcription and APOBECS-driven mutagenesis on loss of Vif function. We will determine the rate of Vif inactivation as result of either reverse transcriptase or cytidine deamination induced mutations on a single cell level using assays based on fluorescence tagged APOBEC3G degradation. Variation in Vif function may influence the pathogenicity of HIV-1 by rendering its genome more or less resistant to deaminase activity and these studies have the potential to reveal how Vif mediated protection from cytidine deamination is modulated in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064001-05
Application #
7369738
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2005-06-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$354,743
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Young, George R; Terry, Sandra N; Manganaro, Lara et al. (2018) HIV-1 Infection of Primary CD4+ T Cells Regulates the Expression of Specific Human Endogenous Retrovirus HERV-K (HML-2) Elements. J Virol 92:
Alvarez, Raymond A; Maestre, Ana M; Law, Kenneth et al. (2017) Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG. JCI Insight 2:e88226
Ooms, Marcel; Letko, Michael; Simon, Viviana (2017) The Structural Interface between HIV-1 Vif and Human APOBEC3H. J Virol 91:
Terry, Sandra N; Manganaro, Lara; Cuesta-Dominguez, Alvaro et al. (2017) Expression of HERV-K108 envelope interferes with HIV-1 production. Virology 509:52-59
Hultquist, Judd F; Schumann, Kathrin; Woo, Jonathan M et al. (2016) A Cas9 Ribonucleoprotein Platform for Functional Genetic Studies of HIV-Host Interactions in Primary Human T Cells. Cell Rep 17:1438-1452
Watanabe, Susan M; Simon, Viviana; Durham, Natasha D et al. (2016) The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility. Retrovirology 13:64
Reddy, Kavidha; Ooms, Marcel; Letko, Michael et al. (2016) Functional characterization of Vif proteins from HIV-1 infected patients with different APOBEC3G haplotypes. AIDS 30:1723-9
Simon, Viviana; Bloch, Nicolin; Landau, Nathaniel R (2015) Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat Immunol 16:546-53
D'arc, Mirela; Ayouba, Ahidjo; Esteban, Amandine et al. (2015) Origin of the HIV-1 group O epidemic in western lowland gorillas. Proc Natl Acad Sci U S A 112:E1343-52
Letko, Michael; Booiman, Thijs; Kootstra, Neeltje et al. (2015) Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface. Cell Rep 13:1789-99

Showing the most recent 10 out of 34 publications