Brodie S, Lewinsohn D, Patterson B, Ryncarz A, Corey L, Greenberg P, Riddell S; University of Washington, Seattle.
The persistence of HIV replication in in vivo has been suggested to reflect an inadequate CTL response. The antiviral activity of HIV-specific CTL, duration of persistence, and the ability of these effector cells to migrate in vivo to sites of infection was assessed by expanding autologous HIV gag-specific CD8+ CTL in vitro and adoptively transferring these CTL to HIV-infected individuals. Therapy consisted of 5 CTL infusions, the final two infusions containing cells transduced with a single copy of the neomycin phosphotransferase gene (neo). Plasma and PBMC were assayed for HIV RNA at sequential time points before, during, and after infusions and a lymph node was biopsied 4 days after the final neo infusion. We show that the transferred CTL retained lytic function in vivo, accumulated adjacent to HIV-infected cells in lymph nodes, and transiently reduced the levels of circulating productively infected CD4+ T cells. Neo was found exclusively in CD8+ T cells: as many as 3.5% in blood and 8% in lymph node contained neo within 24 h and 4 days of infusion, respectively, and were fully cleared from blood within 2 to 3 weeks. One explanation for the brief persistence of CTL in vivo is the absence of an adequate HIV-specific CD4 Th response. in vitro, HIV-specific CTL require CD4 T cell help and/or exogenous IL-2 to proliferate after stimulation with antigens. in vivo studies are currently underway to assess the effects of IL-2 given concurrently with adoptive CTL therapy. Collectively, these results provide direct evidence that HIV-specific CTL target sites of HIV replication and mediate antiviral activity, and suggest that the development of immunotherapeutic approaches to sustain a strong CTL response may be a useful adjunct to treatment of HIV infection.
Keywords: AEGIS, HIV-1, T-Lymphocytes, Cytotoxic, HIV, HIV Infections, Antigens, CD4, Virus Replication, Antigens, CD8, Emigration and Immigration, HIV Antigens, Lymph Nodes, Interleukin-2, in vitro, virology, AIDS
