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.

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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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants Phase II (R33)
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Special Emphasis Panel (NSS)
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Sharma, Opendra K
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Yale University
Schools of Medicine
New Haven
United States
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Nguyen, Henry C; Yang, Haitao; Fribourgh, Jennifer L et al. (2015) Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex. Structure 23:441-9
Fribourgh, Jennifer L; Nguyen, Henry C; Wolfe, Leslie S et al. (2014) Core binding factor beta plays a critical role by facilitating the assembly of the Vif-cullin 5 E3 ubiquitin ligase. J Virol 88:3309-19
Wolfe, Leslie S; Stanley, Bradford J; Liu, Chang et al. (2010) Dissection of the HIV Vif interaction with human E3 ubiquitin ligase. J Virol 84:7135-9
Zhang, Wenyan; Du, Juan; Yu, Kevin et al. (2010) Association of potent human antiviral cytidine deaminases with 7SL RNA and viral RNP in HIV-1 virions. J Virol 84:12903-13
Yang, Haitao; Wang, Jimin; Jia, Xiaofei et al. (2010) Structural insight into the mechanisms of enveloped virus tethering by tetherin. Proc Natl Acad Sci U S A 107:18428-32
Zhen, Anjie; Wang, Tao; Zhao, Ke et al. (2010) A single amino acid difference in human APOBEC3H variants determines HIV-1 Vif sensitivity. J Virol 84:1902-11