Human Immunodeficiency Virus Type 1 (HIV-1) infects CD4-positive T cells and monocytes/macrophages and cause Acquired Immune Deficiency Syndrome (AIDS) in humans. Research proposed in this application is focusing on the cellular factors that resist HIV-1 infection that are activated immediately after HIV enters cells. These proteins are cellular cytidine deaminases (called APOBEC proteins) that convert cytosines to uracils on genomic targets and play important roles in protein metabolism and immune responses. The critical factor for our study is the recent finding that APOBEC3 proteins modify HIV-1 viral genomes and thus block their replication. This potent protective mechanism is circumvented by HIV-1 (and other primate lentiviruses) by their production of a viral infectivity factor, Vif. Vif renders the APOBEC3 proteins inactive and thus allows viral infection. These exciting discoveries have uncovered a fierce battlefield between retroviruses and intracellular immune networks. At the same time, these interactions provide for a unique and novel opportunity to exploit APOBEC3 proteins as new tools for anti-HIV therapeutics. Our long-term objective is to develop successful therapeutic treatments for HIV-1 by overcoming the vulnerability of this innate immunity to viral protein Vif. This proposal will address three specific aims: (1) To study the molecular structure of this antiviral innate immunity and identify additional APOBEC3 family members;(2) To study the enzymatic complex of APOBEC3 proteins and determine the cellular cofactors present in the putative editosome;(3) To define the precise mechanism by which Vif disrupts this innate intracellular immunity by binding to and destroying APOBEC3s. This project will lead to a definition of the architecture of this innate immune system, and will also lead to a full understanding of the antiviral mechanism during infection. Importantly, we will identify the molecular determinant(s) usurped by Vif to counteract this immunity. New therapeutic targets will be discovered to help us repair the vulnerable aspect of this immunity so it can constitutively function during HIV infection. Such findings may provide a more effective modality for the treatment of HIV infection to be used in conjunction with other chemotherapy and vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Sharma, Opendra K
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Michigan State University
Schools of Osteopathic Medicine
East Lansing
United States
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Zhou, Tao; Frabutt, Dylan A; Moremen, Kelley W et al. (2015) ERManI (Endoplasmic Reticulum Class I α-Mannosidase) Is Required for HIV-1 Envelope Glycoprotein Degradation via Endoplasmic Reticulum-associated Protein Degradation Pathway. J Biol Chem 290:22184-92
Zhou, Tao; Dang, Ying; Zheng, Yong-Hui (2014) The mitochondrial translocator protein, TSPO, inhibits HIV-1 envelope glycoprotein biosynthesis via the endoplasmic reticulum-associated protein degradation pathway. J Virol 88:3474-84
Zhou, Tao; Dang, Ying; Baker, Jacob J et al. (2012) Evidence for Vpr-dependent HIV-1 replication in human CD4+ CEM.NKR T-cells. Retrovirology 9:93
Zheng, Yong-Hui; Jeang, Kuan-Teh; Tokunaga, Kenzo (2012) Host restriction factors in retroviral infection: promises in virus-host interaction. Retrovirology 9:112
Abudu, Aierken; Wang, Xiaojun; Dang, Ying et al. (2012) Identification of molecular determinants from Moloney leukemia virus 10 homolog (MOV10) protein for virion packaging and anti-HIV-1 activity. J Biol Chem 287:1220-8
Wang, Xiaojun; Abudu, Aierken; Son, Sungmo et al. (2011) Analysis of human APOBEC3H haplotypes and anti-human immunodeficiency virus type 1 activity. J Virol 85:3142-52
Dang, Ying; Abudu, Aierken; Son, Sungmo et al. (2011) Identification of a single amino acid required for APOBEC3 antiretroviral cytidine deaminase activity. J Virol 85:5691-5
Dang, Ying; Davis, Roderick W; York, Ian A et al. (2010) Identification of 81LGxGxxIxW89 and 171EDRW174 domains from human immunodeficiency virus type 1 Vif that regulate APOBEC3G and APOBEC3F neutralizing activity. J Virol 84:5741-50
Dang, Ying; Wang, Xiaojun; York, Ian A et al. (2010) Identification of a critical T(Q/D/E)x5ADx2(I/L) motif from primate lentivirus Vif proteins that regulate APOBEC3G and APOBEC3F neutralizing activity. J Virol 84:8561-70
Wang, Xiaojun; Han, Yanxing; Dang, Ying et al. (2010) Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication. J Biol Chem 285:14346-55

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