HIV-related Research Overview Steve Zeichner, MD, PhD Sr. Investigator, Division of Cancer and Immunology Children’s Research Institute, Children’s National Medical Center Assoc. Prof., Dept of Pediatrics & Microbiology, GWUMC SZeichne@cnmc.org 202-884-6131

Research Areas HIV basic virology KSHV basic virology Virus-host cell interactions Effect of viral genes on the host cell Cellular genes involved in the maintenance and control of HIV latency KSHV basic virology Control of KSHV gene expression Clinical studies on pediatric HIV disease

Effect of Vpr on Host Cell Gene Expression

Models for Vpr-mediated Cell Cycle Arrest

Hierarchical clustering of differentially expressed host cell genes before and after induction of lytic infection in ACH-2 cells. Ras and Ras-related genes upregulated in lytically replicating ACH-2. Abl-kinase regulates Ras. Ras and abl-kinase synergistically activate NF-kB. NF-kB is a key positive regulator of HIV gene expression. Can an abl-kinase inhibitor inhibit HIV replication? Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005 Jul;11(7):731-9. Epub 2005 Jun 26

Conclusions Latently infected cell lines show differences in cell gene expression compared to parental cells before lytic replication. Agents targeting products of genes differentially expressed in latently infected cells can eject HIV from latency. Such studies may suggest new ways of manipulating HIV latency, which might find clinical utility in studies aimed at assessing efficacy of reservoir reduction.

Effect of the Viral DNA Replication Inhibitor Cidofovir On the Viral Gene Expression Pattern Color: - CDV Black: + CDV