Our Science – Yarchoan Website
Robert Yarchoan, M.D.
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-associated herpesvirus (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 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.
We are also studying the pathogenesis of KSHV-associated MCD and related disorders. As part of of this effort, we are studying the cytokine dysregulation in MCD and its association with symptomatology. We have also recently identified a new MCD-like syndrome caused by KSHV in which patients have inflammatory symptoms similar to those of MCD, have increase KSHV viral IL-6 levels, but do not have pathological findings of MCD. This syndrome, which we are calling KSHV-associated inflammatory cytokine syndrome (KICS), may account for otherwise unexplained fevers in certain patients with HIV and KSHV co-infection.
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 clinical trials of IL-12, an agent with anti-angiogenic and immunologic activity, in KS and 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 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 2/26/2013.