Abstract

To fully understand the pathogenic process of human viral diseases animal? models are needed. We have developed the SCID-hu mouse as an in vivo? system which demonstrates HIV-l-induced pathology closely resembling that? seen in human disease. The SCID-hu system employs immunodeficient mice as? hosts for human fetal hematopoietic tissue (thymus/liver) grafts, which? can be maintained for up to a year. We recently found that these human? Thy/Liv grafts in HIV-l-infected SCID-hu mice undergo marked depletion of? CD4-positive cells in a manner characteristic of that seen in human HIV-l? infection. Thus, we have a model uniquely suited to the study of HIV-I? pathogenesis in vivo which avoids the artifacts common to in vitro? systems. We will use this model to investigate the molecular mechanisms? used by HIV-l to deplete human thymocytes in vivo and will also introduce? viruses mutated in the auxiliary genes, nef, vif, vpu, and vpr, to? determine the role these genes play in the pathogenic process. Our? preliminary data indicate that nef mutants of HIV-l display attenuated? growth and cytopathic properties when compared to wild-type virus in this? system. Thus, the SCID-hu mouse appears to function as an in vivo system? to assess attenuation of HIV-l strains. Site-directed mutations in? previously identified """"""""active"""""""" regions and/or deletion mutants of the nef? gene will be introduced into infectious virus and used in the SCID-hu? system to determine the critical regions of nef in vivo. These experiments? should increase our knowledge of how HIV-l depletes cells in a lymphoid? organ, and provide valuable information regarding the role of viral? auxiliary genes on virus replication in vivo. These studies will also help? to develop the SCID-hu system as a means of screening """"""""attenuated"""""""" viruses? which may augment the development of a live attenuated vaccine against? AIDS.?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI036059-14
Application #
7234101
Study Section
Special Emphasis Panel (NSS)
Program Officer
Young, Janet M
Project Start
1994-09-01
Project End
2008-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
14
Fiscal Year
2007
Total Cost
$361,494
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Vatakis, Dimitrios N; Nixon, Christopher C; Bristol, Gregory et al. (2009) Differentially stimulated CD4+ T cells display altered human immunodeficiency virus infection kinetics: implications for the efficacy of antiviral agents. J Virol 83:3374-8
Vatakis, Dimitrios N; Kim, Sanggu; Kim, Namshin et al. (2009) Human immunodeficiency virus integration efficiency and site selection in quiescent CD4+ T cells. J Virol 83:6222-33
Marsden, Matthew D; Xu, Jie; Hamer, Dean et al. (2008) Short communication: Activating stimuli enhance immunotoxin-mediated killing of HIV-infected macrophages. AIDS Res Hum Retroviruses 24:1399-404
Vatakis, Dimitrios N; Bristol, Gregory; Wilkinson, Thomas A et al. (2007) Immediate activation fails to rescue efficient human immunodeficiency virus replication in quiescent CD4+ T cells. J Virol 81:3574-82
Marsden, Matthew D; Zack, Jerome A (2007) Human immunodeficiency virus bearing a disrupted central DNA flap is pathogenic in vivo. J Virol 81:6146-50
Arlen, Philip A; Brooks, David G; Gao, Lian Y et al. (2006) Rapid expression of human immunodeficiency virus following activation of latently infected cells. J Virol 80:1599-603
Chang, Margaret; Brown, Helen J; Collado-Hidalgo, Alicia et al. (2005) beta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA. J Virol 79:13538-47
Kitchen, Scott G; Whitmire, Jason K; Jones, Nicole R et al. (2005) The CD4 molecule on CD8+ T lymphocytes directly enhances the immune response to viral and cellular antigens. Proc Natl Acad Sci U S A 102:3794-9
Moore, John P; Kitchen, Scott G; Pugach, Pavel et al. (2004) The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 20:111-26
Kitchen, Scott G; Jones, Nicole R; LaForge, Stuart et al. (2004) CD4 on CD8(+) T cells directly enhances effector function and is a target for HIV infection. Proc Natl Acad Sci U S A 101:8727-32

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