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MARIO OSTROWSKI, M.D.
HIV and HCV immunopathogenesis, HIV vaccine design, dendritic cell biology, immunotherapeutics
|Clinical Sciences Division|
University of Toronto
Medical Sciences Building, Rm 6271
1 King's College Circle
Toronto, ON M5S 1A8
Our research program deals with investigating the mechanisms of chronic persistence of human virus infections like HIV or HCV within their hosts, from an immunologic perspective.
In addition, we are developing novel strategies to aid in vaccine design to enhance cellular immunity to persistent viruses with an emphasis on dendritic cell modulation. Finally, we are interested in studying the role of new immunotherapies in HIV and HCV infection.
HIV and HCV Immunopathogenesis
1. We are particularly interested in defining the role of HIV specific immunity in controlling HIV replication in vivo. Current evidence supports the hypothesis that HIV-1 specific memory CD4+ T cells are defective both qualitatively ('anergic state') and quantitatively in infected individuals. We have characterized the maturation phenotype of HIV-1 specific CD4+ T cells in comparison to CMV specific CD4+ T cells in HIV-1 infected individuals or HIV-1 uninfected individuals and have shown that HIV-1 specific CD4+ T cells are of an immature phenotype compared to those against CMV. We have investigated the apoptotic potential of HIV-1 specific memory CD4+ T cells in comparison to CMV specific CD4+ T cells in HIV-1 infected individuals and have found that HIV-1 specific CD4+ T cells are preferentially undergoing apoptosis ex vivo, suggesting an added mechanism for lack of immune containment. Our current studies will involve extensively characterizing HIV-1 specific CD4+T cell epitopes during acute HIV-1 infection and in longterm nonprogressors using new CD4+ T cell cloning and tetramer technologies in order to
a) identify protective epitopes to advance vaccine development;
b) to further explore mechanisms of anergy.
2. We have started to characterize ex vivo human intrahepatic immune responses in HCV and HIV-1/HCV co-infection in order to better understand why co-infected individuals progress more rapidly to cirrhosis.
3. We are currently using genetic profiling and bio-informatics to characterize a systems-genetic phenotype of T cells in uncontrolled versus controlled HIV-1 infection,in order to better understand mechanisms of CD4 T cell decline and loss of immune control.
HIV Vaccine design, dendritic cell biology
Canarypox vectors are currently licensed vaccines used to induce cellular immunity, which appear to have only mild immunogenicity in vivo. We are currently using a strategy of incorporation of the TNF superfamily molecules, CD40L, RANKL, or Ox40L into the canarypox vectors in order to determine whether we can enhance the ability of standard canarypox vaccines to induce cellular immunity against HIV or SIV. We will use in vitro human dendritic cells, murine and rhesus macaque systems to test our hypotheses.