Stephen Dewhurst, Ph.D.

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Current research interests in my laboratory include the following:

HOST ADAPTATION BY EMERGING INFLUENZA VIRUSES: ROLE OF THE VIRUS POLYMERASE: Influenza A virus (IAV) replicates in the upper respiratory tract of humans at 33oC and in the intestinal tract of birds at close to 41oC. The viral RNA polymerase complex comprises three subunits (PA, PB1 and PB2) and plays an important role in host adaptation. We have shown that polymerase complexes containing the H5N1 or avian PB2 protein retained transcriptional activity over a broad temperature range (30-42oC), whereas complexes containing a mammalian IAV PB2 protein lost activity at elevated temperatures (over 39oC). These results show that PB2 may regulate the temperature optimum for IAV RNA polymerase activity. Current studies are examining the biochemical properties of the 1918 IAV RNA polymerase, and interactions between the polymerase subunits. This work is supported by the UR's New York Influenza Center of Excellence (NYICE), one of 6 national centers that are part of the CEIRS consortium (Centers of Excellence for Influenza Research and Surveillance).

HIV VACCINE DEVELOPMENT: We are using bacteriophage lambda as a scaffold to display the HIV-1 envelope glycoprotein in a dense, repetitive array that is expected to elicit more potent humoral immune responses against this key virus antigen. We are also testing two other vaccine concepts. The first seeks to produce a vaccine or microbicide capable of preventing the sexual transmission of HIV-1 infection. This project is focussed on cationic amyloid fibrils present in semen, termed semen-derived enhancer of viral infection (SEVI), that bind HIV-1 virions and enhance viral infectivity by several orders of magnitude. We hypothesize that virus-SEVI complexes represent potential vaccine or microbicide targets. The second project addresses the fact that HIV vaccines tested to date do not elicit broadly neutralizing antibody (BNA) responses. To address this problem, we are developing antigenic mimics of sequestered, conformational epitopes on HIV-1 Env, which can then be used as immunogens to elicit BNA.

NEUROAIDS RESEARCH: CEREBROVASCULAR EFFECTS OF METHAMPHETAMINE AND NOVEL THERAPEUTIC APPROACHES: Methamphetamine (MA) abuse is associated with cerebrovascular complications, including stroke, and MA abuse has also been associated with the exacerbation of HIV-1 associated neurologic disease (HAND). We have shown that MA exposure results in a profound inhibition of cerebral blood flow, and a decline in cerebral oxygenation. This has important implications for how MA may exacerbate the pathogenesis of HAND. We are presently examining the effect of MA exposure on cerebral blood flow and tissue oxygenation, both in wild-type mice and in the context of HIV-1 associated neuroinflammation, using transgenic mouse models for HIV/AIDS. Future studies, in collaboration with Karl Kasischke, will include use of two-photon imaging methods to assess local blood flow and neuronal oxidative metabolism. A second neuroAIDS project seeks to develop new therapies for HAND, which remains a major clinical problem in HIV-infected persons even in the post-HAART era. Our approach is to develop protective approaches by targeting mixed lineage kinase (MLK)-3, an upstream kinase that regulates the activity of pro-apoptotic and pro-inflammatory kinases that include Jun N-terminal kinase (JNK).

Current Appointments

• Chairman - Department of Microbiology and Immunology (SMD)
• Dean's Professorship - Department of Dean's Office, SMD (SMD)
• Professor - Department of Microbiology and Immunology (SMD)

Lab Description

Our major areas of research focus are: HIV vaccine development; therapeutic approaches to NeuroAIDS; generation of novel oncolytic virus vectors; and influenza virus research.

Lab Website

http://128.151.146.193/