Gene Therapy Laboratory
Treatment of AIDS with genetically modified blood stem cells hypothesizes that genetic modification of cells containing inhibitors of genes important for HIV-1 replication will prevent the progression of HIV-1 in these cell populations and slow the progression to disease. Of the various ways that this could be tested, one approach currently tests whether genetically transduced blood stem cells could repopulate in the host after autologous transplantation and result in mixed blood chimerism (host cells plus genetically modified host cells).
A second approach addresses whether autologous CD4 T-cells can be genetically modified and safely transferred to AIDS patients. We are seeking to answer three important questions: (1) Can lentivirus-transduced cells be safely transplanted into AIDS patients without serious procedure-related morbidity? (2) Which potential HIV targets are most susceptible to a transgene attack? (3) Can a selection system be introduced with the anti-HIV transgenes to produce long-term expression of the transgene?
Cytomegalovirus Infection (CMV)
Despite available antiviral agents for use in prevention of CMV infection after transplantation, the virus remains a problem for efficient patient management after both solid organ and marrow transplantation. The pathogenesis of infection in this setting involves transfer of infection with the transplanted organ or reactivation of endogenous infection. Once infection occurs, CMV encodes several proteins that interfere with antigen processing and HLA-associated transport of peptide epitope to the cell surface, a process necessary for induction of cytotoxic T-lymphocyte (CTL) function. We are studying cellular mechanisms of host protection after stem cell transplantation. Our laboratory is developing new methods of DNA-based immunization for CMV. It is likely that antiviral chemotherapy will not be sufficient to protect immunosuppressed patients from endogenous CMV infection, and it is possible that methods that strengthen the host's resistance to infection will have an increasing role in controlling CMV infection in the future.