Recent advances on retroviral research that members of APOBEC3 (A3) subfamily proteins potently blocks replication of retroviruses have opened a new avenue for the development of antiretroviral therapy for human immunodeficiency virus type 1 (HIV-1) infection. This subfamily includes A3A, A3B, A3C, A3DE, A3F, A3G and A3H, which belong to the cytidine deaminase family. They are incorporated into viral particles during viral assembly and disrupt viral reverse transcription to inhibit viral replication. As a counteraction, HIV-1 produces a viral infectivity factor, Vif, to destruct most of the A3 proteins via the proteasomal pathway by serving as a bridge between these proteins and a Cullin 5-based E3 ubiquitin ligase. Although these discoveries are exciting, the field desires for further understanding of how this A3-mediated immunity blocks retroviral infection and why it is so vulnerable to Vif. Our long-term goal is to understand how host factors that contribute to the innate immunity to retroviral infection can be effectively targeted for improved treatment of HIV-1 infection. Our objective in this proposal is to further study the antiretroviral mechanism of A3 protein and the process of their proteasomal degradation triggered by Vif. Our rationale is that a new anti-HIV-1 therapy could be developed if we can find a strategy to express A3 proteins that become insensitive to Vif. We propose the following three specific aims: 1) To study the antiretroviral activity of human A3H;2) To study the antiretroviral cofactor for A3G;3) To study the ubiquitin-independent proteasomal degradation of A3G. This project is innovative in that, it offers an opportunity to fully define the architecture of A3-mediated antiretroviral immunity by understanding the function of A3H. It will significantly advance our knowledge by precisely defining the mechanisms related to A3 antiretroviral activity and their degradation in proteasomes. At the completion of this project, it is our expectation that we will be able to not only address these fundamental issues, but also demonstrate the feasibility to employ this immunity to combat HIV-1 infection. Such findings will contribute to 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 Scientist Development Award - Research (K02)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
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Miller, Roger H
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Michigan State University
Schools of Osteopathic Medicine
East Lansing
United States
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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
Dang, Ying; Wang, Xiaojun; Zhou, Tao et al. (2009) Identification of a novel WxSLVK motif in the N terminus of human immunodeficiency virus and simian immunodeficiency virus Vif that is critical for APOBEC3G and APOBEC3F neutralization. J Virol 83:8544-52

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