Section: Research

Postdoctoral Position Available

Mario Stevenson, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Program in Molecular Medicine

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Molecular Genetics and Microbiology
   Program in Immunology and Virology

Pathogenesis of Primate Lentiviruses, Especially HIV

The laboratory focuses on the Pathogenesis of Primate Lentiviruses and especially HIV. We exploit biochemical genetic and cellular approaches to understand the functions of viral accessory genes including Nef and Vpr/Vpx as well as structural virion proteins including gag and the roles these proteins play in intracellular trafficking of the virus and their roles in mediating the pathogenic effects of viral infection. One of the more intriguing features of HIV is its ability to infect and replicate within non-cycling cells. This property of HIV is dictated by nucleophilic viral proteins which chaperone viral nucleic acids into the nucleus . In non-dividing cells, these nucleophilic proteins allow to the virus to bypass the nuclear envelope that is normally a barrier to cell infection by simpler retroviruses. We have been exploring the role of gag and the Vpr/Vpx proteins in mediating nuclear uptake of viral DNA. It is now becoming apparent that these proteins may exhibit nuclear cytoplasmic shuttling activities that we have important roles in virus replication both at the level of virus entry and at the level of virus production.

Nef is an accessory protein which, although dispensable for viral replication in cell lines in vitro, appears critical for viral replication and pathogenicity in vivo. We are currently exploring the hypothesis that Nef promotes viral dissemination. Our hypothesis is that Nef has evolved function in macrophages and that promotes for recruitment of substrate T cells to sites of infection. We have evidence that Nef induces the establishment of chemotaxis gradients around macrophages which promote T cell recruitment and additional, that Nef induces the release of an as yet unidentified factor that renders T cells highly permissive to infection. Nef appears to mediate these biological activities through the CD40 receptor. We suspect that the mimicry of CD40 by Nef may contribute to some of the pathogenic effects of viral replication. CD40 is normally tightly regulated because it controls the release of pro-inflammatory cytokines. Therefore, it is possible that its continued stimulation of CD40 by Nef may result in a more protracted release of pro-inflammatory cytokines from infected macrophages and that this would have a negative impact on host function.

Through the use of highly active antiretroviral therapy, HIV replication can be dramatically suppressed in the infected individuals. However, it is now becoming apparent that there are long-lived reservoirs of virus-infected cells that persisted in the face of therapy. The laboratory is interested in characterizing the nature of the reservoir that supports persistent viral replication. We are examining how HIV genes may impact macrophage function so as to enhance their ability to serve as long lived reservoirs for HIV.

Phone: 508 856 4581
E-mail: Mario.Stevenson@umassmed.edu
Keywords: Intracellular Trafficking, Virology, Infectious Disease

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Stevenson for additional details.