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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.
IS PRIMATE LENTIVIRUS DISSEMINATION
MACROPHAGE DEPENDENT?
Figure Legend
The diagram proposes a model in which an antigen-presenting cell such as a macrophage
upon HIV-1 infection, undergoes a physiological change which promotes recruitment of T
cells to the site of infection. Studies in the laboratory suggest that b-chemokines, MIP-1a and MIP-1b are induced upon HIV-1 infection. Our studies implicate a specific
viral gene product in promoting chemokine release, a consequence of this chemokine
production is the formation of macrophage T cell conjugates through which dissemination
of virions from the infected macrophage to uninfected T cells occurs. This method of
cell-to-cell transfer is expected to be an extremely efficient mechanism for viral
dissemination and may protect virions from immune clearance mechanisms of the host.
In addition, the infected macrophage may allow long-term viral persistence in the face
of highly active antiretroviral therapy. This model, if correct, has considerable
implications for the understanding and treatment of HIV infection of humans.
Recent Publications
Hirsch, V.M., Sharkey, M., Brown, C., Brichacek, B., Goldstein, S., Wakefield, R., Byrum, R., Elkins, W., Hahn, B., Lifson, J., Stevenson, M. Vpx is required for dissemination and pathogenesis of SIVSM PBj: Evidence of macrophage-dependent viral amplification. Nat. Med. 1998; 4(12):14011408
Bukrinskaya A, Brichacek B, Mann A, Stevenson M. Establishment of a functional human immunodeficiency virus type 1 (HIV-1) reverse transcription complex involves the cytoskeleton. J Exp Med. 1998 Dec 7;188(11):2113-25.
Swingler S, Mann A, Jacque J, Brichacek B, Sasseville VG, Williams K, Lackner AA, Janoff EN, Wang R, Fisher D, Stevenson M. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nat Med. 1999;5(9):997-103.
Dupont, S., Sharova, N., DeHoratius, C., Virbasius, C-M., Zhu, X., Bukrinskaya, A., Stevenson, M., Green, M. A novel nuclear export activity in HIV-1 matrix protein required for viral replication. Nature 1999; 9(402):681-685
Sharkey ME, Teo I, Greenough T, Sharova N, Luzuriaga K, Sullivan JL, Bucy RP, Kostrikis LG, Haase A, Veryard C, Davaro RE, Cheeseman SH, Daly JS, Bova C, Ellison RT 3rd, Mady B, Lai KK, Moyle G, Nelson M, Gazzard B, Shaunak S, Stevenson M.
Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nat Med. 2000; 6(1):76-81.
Moore JP, Stevenson M. New targets for inhibitors of HIV-1 replication. Nature Reviews Mol Cell Biol. 2000;1(1):40-9.
Somasundaran, M., Sharkey, M., Brichacek, B., Luzuriaga, K., Emerman, M., Sullivan, J., Stevenson, M. Evidence for a cytopathogenicity determinant in HIV-1 Vpr. PNAS In press.
Jacque, J-M., Triques, K., Stevenson, M. Modulation of HIV-1 replication by RNAi. Nature In press.
Potential Rotation Projects
Contact Dr Stevenson for details.
Laboratory Personnel
Mario Stevenson, PhD- Principal Investigator
Kim Departie, Administrator
Lisa Smith, Administrative Assistant
Rajnish Kaushik, Post Doc
Mark Sharkey, Asst. Prof.
Struan Bourke, visiting
Patrick Younan, GSBS
Lue Dai, GSBS
Xiaonan Zhu, GSBS
Yuanfei Wu, Post Doc
Natalia Sharova, Instructor
Ruzena Stanska, Post Doc
Joana Paixo-Monteiro, visiting
Laura Brandano, GSBS
Ann Dauphin, Lab Manager
Simon Swingler, Asst. Prof.
Angela Mann, Asst. Prof.
Academic Background
Mario Stevenson received his PhD from the University of Strathclyde in Glasgow
Scotland in 1984. He performed postdoctoral studies at the University of Nebraska
Medical Center and was a professor at that institution since 1993. He conducted a
research sabbatical at National Institute for Medical Research in London in 1990.
In 1995, he joined the Program in Molecular Medicine at the University of Massachusetts
Medical Center.
Phone: 508 856 4581
E-mail: Mario.Stevenson@umassmed.edu
Keywords:
Intracellular Trafficking,
Virology,
Infectious Disease
Postdoctoral Position Available
A postdoctoral position is available to study in this laboratory.
Contact Dr. Stevenson for additional details.
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373 Plantation Street Worcester, MA 01605