Our group is principally concerned with the molecular biology of HIV pathogenesis, particularly the pathogenesis of pediatric HIV disease. The course of HIV disease in pediatric patients differs substantially from the course of disease in adults. We are therefore particularly interested in trying to understand the involvement of host cell factors in HIV replication and the effect of HIV infection on the host cell. Our underlying hypothesis holds that there is one set of cellular conditions that is ideal for normal cellular growth and replication, that another set of conditions is ideal for viral replication, and that viruses (particularly HIV) have evolved ways of altering their host cells to enhance viral replication. During the past year, we have used cDNA microarray technology to begin to compile a comprehensive catalog of the cellular genes with altered expression during HIV replication and to attribute the changes in cellular gene expression to particular stages of the viral replication cycle and individual viral gene products. In support of our hypothesis, several cellular genes that are differentially regulated in the presence of particular viral gene products have previously characterized relationships to HIV replication. We have also constructed small arrays containing the entire set of genes from several herpesviruses, including the Kaposi's sarcoma-associated herpesvirus HHV8, and are using these tools to obtain a comprehensive description of the viral transcription programs and the cellular responses to viral infection.In other studies, we have partially cloned and have begun to characterize a cellular factor that binds to a site in the HIV LTR which is not active in lymphocytic cells, but is active in certain differentiated cell types. The factor appears to have an interesting pattern of tissue expression and interesting activities in addition to its sequence-specific DNA binding activity. Further studies aimed at completing the cloning of the factor and understanding its additional activities are in progress. In our clinical work, we have shown that peripheral blood lymphocyte telomeres shorten more rapidly during the first years of life, suggesting that lymphocytes turnover more rapidly during infancy than later in life. This may provide an explanation for the higher HIV viral loads and more rapid disease progression observed in pediatric HIV patients. It is 100% AIDS research. (About 10% of the work is also related to cancer.)

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010087-04
Application #
6433425
Study Section
(HAMB)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Yoshizuka, Naoto; Yoshizuka-Chadani, Yuko; Krishnan, Vyjayanthi et al. (2005) Human immunodeficiency virus type 1 Vpr-dependent cell cycle arrest through a mitogen-activated protein kinase signal transduction pathway. J Virol 79:11366-81
Taylor, Perdita; Worrell, Carol; Steinberg, Seth M et al. (2004) Natural history of lipid abnormalities and fat redistribution among human immunodeficiency virus-infected children receiving long-term, protease inhibitor-containing, highly active antiretroviral therapy regimens. Pediatrics 114:e235-42
Krishnan, Vyjayanthi; Zeichner, Steven L (2004) Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency. J Virol 78:9458-73
Bentley, K; Deacon, N; Sonza, S et al. (2004) Mutational analysis of the HIV-1 LTR as a promoter of negative sense transcription. Arch Virol 149:2277-94
Hazra, Rohan; Balis, Frank M; Tullio, Antonella N et al. (2004) Single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected children. Antimicrob Agents Chemother 48:124-9
Suscovich, Todd J; Paulose-Murphy, Mini; Harlow, Jason D et al. (2004) Defective immune function of primary effusion lymphoma cells is associated with distinct KSHV gene expression profiles. Leuk Lymphoma 45:1223-38
Tamula, Mary Anne Toledo; Wolters, Pamela L; Walsek, Claire et al. (2003) Cognitive decline with immunologic and virologic stability in four children with human immunodeficiency virus disease. Pediatrics 112:679-84
Nakamura, Hiroyuki; Lu, Michael; Gwack, Yousang et al. (2003) Global changes in Kaposi's sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator. J Virol 77:4205-20
Shibata, R; Feng, Y R; Gee, D et al. (1999) Telomere dynamics in monkeys: increased cell turnover in macaques infected with chimeric simian-human immunodeficiency viruses. J Med Primatol 28:1-10
Feng, Y R; Biggar, R J; Gee, D et al. (1999) Long-term telomere dynamics: modest increase of cell turnover in HIV-infected individuals followed for up to 14 years. Pathobiology 67:34-8

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