Our Science – Yarchoan Website

Robert Yarchoan, M.D.

HIV and AIDS Malignancy Branch Head, Retroviral Disease Section Branch Chief Building 10, Room 6N106 NCI-Bethesda MSC 1868 Bethesda, MD 20892-1868 Phone:   301-496-0328 Fax:   Fax Number not listed E-Mail:   yarchoan@helix.nih.gov Link: Other Homepage

Biography

Dr. Robert Yarchoan received his B.A. from Amherst College with a major in biophysics and his M.D. from the University of Pennsylvania. He trained in internal medicine at the University of Minnesota and Immunology in the Metabolism Branch, NCI. He then joined the laboratory of Dr. Samuel Broder, where he played a major role in the development of the first effective therapies for HIV infection, including zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC). In particular, he led the first clinical trials of these drugs, was a co-inventor of didanosine and zalcitabine as AIDS therapies, and led initial studies of combination anti-HIV therapy. He was a Section Chief in the Medicine Branch from 1991 to 1996 and was named chief of the newly formed HIV and AIDS Malignancy Branch in 1996. Since that time, he has focused much of his research on AIDS-related malignancies, especially tumors caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Among other honors, he has been awarded the Assistant Secretary for Health Award and the U.S. Public Health Service Outstanding Service Medal, has been inducted as a Fellow of the American Association for the Advancement of Science (AAAS), and is a member of the American Society for Clinical Investigation. In December, 2006, he was a recipient of the first NIH World AIDS Day Award, and in November, 2007, he received the NCI HIV/AIDS Research Excellence Award along with Drs. Samuel Broder, Robert C. Gallo, and Hiroaki Mitsuya. In December 2007, Dr. Yarchoan also was appointed as the first Director of the NCI Office of HIV and AIDS Malignancy. This office, which is in the Office of the Director, NCI, has a major role in coordinating and prioritizing the HIV/AIDS research portfolio throughout the NCI.

Research

View Dr. Yarchoan's Current Clinical Trials

The research in the Retroviral Diseases Section includes a laboratory and clinical component, and there is substantial integration and cross-fertilization between these components.

Pathogenesis of virus-associated tumors

One main area of research focus is the study of the pathogenesis of viral-associated tumors, especially those associated with Kaposi's sarcoma-associatedherpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). KSHV is the causal agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). We observed that KS preferentially develops in the feet and other areas of the body with a poor vascular supply. In studying this phenomenon, we discovered that KSHV is induced by hypoxic to undergo lytic replication and to produce factors with direct or indirect angiogenic activity. In further exploring this observation, we found that the genome of KSHV encodes for several hypoxia response elements (HRE) that respond to hypoxia-induced factor (HIF). We are currently exploring the differential upregulation of various KSHV genes by hypoxia and how this may influence the pathogenesis of KSHV-induced tumors. As part of this effort, we are analyzing the genetic organization of the ORF34-ORF37 gene cluster, which includes a phosphotransferase and shut-off exonuclease (SOX). In an extension of this work, we are also exploring the differential upregulation of various cellular genes by two different HIFs, HIF-1 and HIF-2.


Development of novel therapies for AIDS-related malignancies and HIV infection

Another main focus of our research is the development of novel therapies for HIV-related malignancies and HIV infection. This work is informed by the pathogenesis-associated work described above. One area of principal interest is Kaposi's sarcoma (KS). Our group is exploring approaches that are based on an understanding of the pathogenesis of this disease but that do not involve the use of cytotoxic chemotherapy. There is evidence that production of virally encoded and cellular angiogenesis-inducing factors by KSHV-infected cells is important in the pathogenesis of KS, and this makes antiangiogenesis approaches attractive to consider. In the laboratory, we are studying the regulation and activity of these angiogenic factors. We have recently completed a clinical trial of IL-12, an agent with anti-angiogenic and immunologic activity, in KS. We are also completing a study of the combination of IL-12 and a liposomal anthracycline. Our group is also exploring the use of humanized anti-VEGF antibody in KS and have initiated a trial of BAY 43-9006, which blocks VEGF-R3. We recently initiated protocols to explore the pathogenesis and targeted therapy for multicentric Castleman's disease (MCD) and HIV-associated primary central nervous system lymphoma.

We continue to have an interest in developing effective antiretroviral therapy. An important target for such therapy is the HIV protease. This enzyme is a dimer, each half of which contains two cysteines. These cysteines are highly preserved among strains of HIV, and modification of these cysteines by glutathionylation can profoundly increase or suppress the HIV protease activity. In particular, upon exposure to oxidative conditions, glutathionylation of a conserved cysteine at position 95 (Cys 95) at the dimer interface completely shuts off HIV-1 protease activity. Interestingly, HIV-2 protease has no cysteines, but has a conserved methionine at position 95 that acts in a similar manner. Occasional HIV-1-infected patients on long-term protease inhibitor therapy have mutations in Cys 95, and we are attempting to understand the benefit to the virus of this mutation and use this as a tool to understand the role of the Cys 95 regulatory mechanism. We are also attempting to devise therapeutic protease inhibitors that bind to the dimmer interface based on this understanding. Finally, in collaboration with the Vaccine Branch, we have initiated a protocol to study a therapeutic peptide vaccine in HIV infection.

This page was last updated on 6/12/2008.