My goal in seeking a Mentored Research Scientist Development Award (K01) is to develop a career in translational HIV research, integrating basic scientific advances in the field of HIV/AIDS with the development of novel strategies to treat viral infection. As outlined in my research plan, I will focus on the antiviral activity and therapeutic potential of the APOBEC3 host factors, concentrating on the suppressive effect of APOBECS-mediated cytidine deaminase activity on HIV-1 and Hepatitis C virus (HCV) replication in vivo. My ultimate goal is to contribute to our understanding of viral pathogenesis and conceptualize new approaches to infectious disease management, by cultivating and applying my expertise in evolutionary biology, population genetics, and benchtop molecular virology. I will be training and conducting the proposed research in a distinguished and exceptional research environment. This environment will include the University of California San Francisco (UCSF) Department of Medicine, The J. David Gladstone Institute of Virology and Immunology, the San Francisco Veterans Affairs Medical Center (SFVAMC), and the Stanford University School of Medicine Genome Technology Center. This research proposal makes use of a fortuitous synchronicity associated with the treatment of HCV disease in HIV/HCV coinfected individuals. The current standard of treatment for HCV infection is combination therapy with ribavirin and the immunomodulatory cytokine interferon-a (IFN-a). Clinical studies demonstrate that IFN-a treatment results in a pronounced reduction in HIV-1 viral load in addition to its intended antiviral effect against HCV. A number of recent in vitro studies demonstrate that IFN-a treatment strongly induces the expression of the antiviral host factor APOBEC3. We propose to characterize the contribution of APOBEC3 activity to the observed suppression of HIV-1 and HCV viremia in an existing, extensively characterized cohort of HIV/HCV coinfected individuals undergoing IFN-a treatment at the UCSF Medical Center or SFVAMC. The objective of this study is to evaluate APOBEC3 activity as a foundation for novel antiviral treatment strategies, and is therefore directly relevant to public health and the clinical management of HIV and HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA024654-05
Application #
8242881
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2008-05-01
Project End
2013-06-30
Budget Start
2012-05-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$118,002
Indirect Cost
$8,741
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Abdel-Mohsen, Mohamed; Deng, Xutao; Danesh, Ali et al. (2014) Role of microRNA modulation in the interferon-?/ribavirin suppression of HIV-1 in vivo. PLoS One 9:e109220
Abdel-Mohsen, Mohamed; Deng, Xutao; Liegler, Teri et al. (2014) Effects of alpha interferon treatment on intrinsic anti-HIV-1 immunity in vivo. J Virol 88:763-7
Raposo, Rui André Saraiva; Abdel-Mohsen, Mohamed; Deng, Xutao et al. (2014) Dynamic regulation of host restriction factor expression over the course of HIV-1 infection in vivo. J Virol 88:11624-9
Raposo, Rui Andre Saraiva; Abdel-Mohsen, Mohamed; Holditch, Sara J et al. (2013) Increased expression of intrinsic antiviral genes in HLA-B*57-positive individuals. J Leukoc Biol 94:1051-9
Raposo, Rui Andre Saraiva; Abdel-Mohsen, Mohamed; Bilska, Miroslawa et al. (2013) Effects of cellular activation on anti-HIV-1 restriction factor expression profile in primary cells. J Virol 87:11924-9
Pillai, Satish K; Abdel-Mohsen, Mohamed; Guatelli, John et al. (2012) Role of retroviral restriction factors in the interferon-?-mediated suppression of HIV-1 in vivo. Proc Natl Acad Sci U S A 109:3035-40
Skasko, Mark; Tokarev, Andrey; Chen, Cheng-Chang et al. (2011) BST-2 is rapidly down-regulated from the cell surface by the HIV-1 protein Vpu: evidence for a post-ER mechanism of Vpu-action. Virology 411:65-77
Jha, Aashish R; Nixon, Douglas F; Rosenberg, Michael G et al. (2011) Human endogenous retrovirus K106 (HERV-K106) was infectious after the emergence of anatomically modern humans. PLoS One 6:e20234
Smith, Davey M; Zarate, Selene; Shao, Hai et al. (2009) Pleocytosis is associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations. Virology 385:204-8
Yukl, Steven; Pillai, Satish; Li, Peilin et al. (2009) Latently-infected CD4+ T cells are enriched for HIV-1 Tat variants with impaired transactivation activity. Virology 387:98-108

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