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HIV/AIDS
Basic molecular virology and clinical research in the viral pathogenesis program are being conducted in the laboratory of Steven Zeichner, MD, PhD. The molecular pathogenesis studies focus on understanding the interactions of viruses and their host cells, particularly human immunodeficiency virus 1 (HIV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV; Human herpesvirus-8, HHV-8). The HIV research involves studies on how host cell functions contribute to the maintenance of HIV latency. We have shown that cell lines latently infected with HIV exhibit different gene expression patterns than their uninfected parental cells. We hypothesized that these differences resulted from selection for the differential expression of genes that help maintain HIV latency during the production and cloning of the latently infected cell lines. We further hypothesized that treating the latently infected cell lines with small molecule agents that target the products of the differentially expressed genes would eject the virus out of latency, and we showed that the agents could, in fact, activate HIV replication in the latently infected cells. We are now continuing this line of research, identifying additional cellular genes that help control HIV latency and identifying additional small molecule agents targeting the products of those genes that can activate HIV out of latency. We also have studied how certain HIV gene products, such as Vpr, affect host cell physiology and alter host cell signal transduction pathways. This work has additional implications for the pathogenesis and replication strategies of HIV.
The KSHV work involves studies of the viral gene expression program using a purpose-built KSHV long oligonucleotide microarray system we developed. This system enables us to examine the expression of essentially all the genes of KSHV simultaneously. We have used our KSHV microarrays to produce a detailed kinetic description of the KSHV gene expression program and to dissect the KSHV gene expression program using inhibitors of KSHV replication that act as a discrete points in the viral replication cycle. We have also studied the effect of important known KSHV regulatory genes, such as KSHV Rta (ORF50), on the KSHV gene expression program. We are now continuing this work by studying how additional KSHV regulatory genes and selected host cell treatments affect the KSHV gene expression program, and by conducting experiments to understand how such alterations in the KSHV gene expression program may contribute to the pathogenesis of KSHV-associated diseases.
Clinical research projects involve studies of the pathogenesis of pediatric HIV disease and the development of new therapies for pediatric HIV disease. Past studies have included Phase 1 and 2 trials of new antiretroviral agents in children, most recently the nucleotide analog reverse transcriptase inhibitor tenofovir, which determined tenofovir pharmacokinetics and safety in pediatric patients, and described the responses of highly treatment-experienced pediatric HIV patients to tenofovir-containing salvage therapy. Pediatric HIV pathogenesis work included studies of the natural history of lipid abnormalities and lipodystrophy in HIV-infected children treated with protease inhibitors, the effect of antiretroviral therapy on neuropsychological disorders in HIV-infected children and the complications of antiretroviral therapy in pediatric HIV disease.
Contact Information:
Steven Zeichner, MD, PhD
Associate Professor of Pediatrics and Microbiology and Tropical Medicine
George Washington University School of Medicine
Senior Investigator , Division of Cancer and Immunology
Children's Research Institute
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010
Szeichner@cnmc.org
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