The APOBEC3 family comprises seven different proteins (APOBEC3A [A3A] to A3H), which may act as strong mutators of proviral genomes. The accessory HIV protein Vif counteracts the antiviral activity of some but not all APOBEC3 variants. Although the global HIV-1 pandemic is driven by non-B subtypes, in particular subtype C, most data concerning the mode of action of Vif have been derived from subtype B molecular clones in conjunction with A3G. APOBEC3 molecules, however, differ not only in catalytic activity and expression but also in susceptibility to HIV-1 Vif mediated degradation. We hypothesize that broad spectrum Vif activity is the driving force for transmission/establishment of infection while suboptimal Vif activity is essential for emergence of escape variants and diversification in the later stages of disease. This hypothesis will be tested in three complementary specific aims using established and new assays. We will perform a comprehensive analysis of the function of pandemic, non-pandemic and patient- derived Vif alleles (Aim 1), dissect the relationship between Vif evolution and skewed proviral archives in patients (Aim 2), and determine the plasticity of Vif in forced selection experiments by passaging HIV in the presence of increasing APOBEC3 expression (Aim 2). Lastly, we will establish which APOBEC3 restricts viral spread of CXCR4 and CCR5 using viruses encoding mutant Vif variants in a humanized mouse model (Aim 3). These experiments will collectively establish the putative role of Vif as virulence factor, create "genotype to phenotype" assays to predict Vif activity in a subtype specific context and identify specific APOBEC3 proteins relevant for restriction and diversification in vivo. This knowledge will help in the discovery of drugs targeting this diverse viral-host interface and improve the already available treatment options by identifying patients at high risk for viral escape.

Public Health Relevance

This proposal will investigate to what extent Vif alleles representative of all HIV subtypes and Vif variants derived directly from infected individuals differ in their anti-APOBEC3 activities and impact on viral diversification. These findings will allow for differential personalized treatment strategies adapted to the individual's own APOBEC3 repertoire.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Sharma, Opendra K
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Icahn School of Medicine at Mount Sinai
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New York
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Dahabieh, Matthew S; Ooms, Marcel; Brumme, Chanson et al. (2014) Direct non-productive HIV-1 infection in a T-cell line is driven by cellular activation state and NF?B. Retrovirology 11:17
Manganaro, Lara; Pache, Lars; Herrmann, Tobias et al. (2014) Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-?B-dependent manner. J Virol 88:7528-40
Alvarez, Raymond A; Hamlin, Rebecca E; Monroe, Anthony et al. (2014) HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells. J Virol 88:6031-46
Brinzevich, Daria; Young, George R; Sebra, Robert et al. (2014) HIV-1 interacts with human endogenous retrovirus K (HML-2) envelopes derived from human primary lymphocytes. J Virol 88:6213-23
Letko, Michael; Silvestri, Guido; Hahn, Beatrice H et al. (2013) Vif proteins from diverse primate lentiviral lineages use the same binding site in APOBEC3G. J Virol 87:11861-71
Ooms, Marcel; Brayton, Bonnie; Letko, Michael et al. (2013) HIV-1 Vif adaptation to human APOBEC3H haplotypes. Cell Host Microbe 14:411-21
Dahabieh, Matthew S; Ooms, Marcel; Simon, Viviana et al. (2013) A doubly fluorescent HIV-1 reporter shows that the majority of integrated HIV-1 is latent shortly after infection. J Virol 87:4716-27
Ooms, Marcel; Letko, Michael; Binka, Mawuena et al. (2013) The resistance of human APOBEC3H to HIV-1 NL4-3 molecular clone is determined by a single amino acid in Vif. PLoS One 8:e57744
Krupp, Annabel; McCarthy, Kevin R; Ooms, Marcel et al. (2013) APOBEC3G polymorphism as a selective barrier to cross-species transmission and emergence of pathogenic SIV and AIDS in a primate host. PLoS Pathog 9:e1003641
Hultquist, Judd F; Binka, Mawuena; LaRue, Rebecca S et al. (2012) Vif proteins of human and simian immunodeficiency viruses require cellular CBF? to degrade APOBEC3 restriction factors. J Virol 86:2874-7

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