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Session 50 Poster Session Therapeutic Vaccine Studies Session Time: 4:30-6:30 pm Room 4E-F

316-W. Induction of HIV-1-Specific Reactivity in CD8+ and CD4+ T Cells from Patients on Combination Antiretroviral Drug Therapy by Dendritic Cells Loaded with HIV-1-Infected Apoptotic Cells X-Q. Zhao1, X. L. Huang1, L. Borowski1, P. Gupta1, Z. Fan1, S. Watkins1, E. Thomas2, and C. Rinaldo Jr.*1 1Univ. of Pittsburgh, PA and 2Immunex Corp., Seattle, WA Background: Efficient control of HIV-1 infection during combination antiviral drug therapy may require recovery of anti-HIV-1 T-cell responses to residual, autologous virus. We have developed a model for induction of anti-HIV-1 responses in CD8+ and CD4+ T cells of treated subjects by dendritic cells (DC) loaded with various forms of HIV-1 antigens. Methods: Immature, blood monocyte-derived DC (iDC) from 7 late stage patients on combination drug therapy and 1 untreated, slow progressor, were loaded in vitro with autologous, CD8 negative, apoptotic (AP), or necrotic (NE) cells that contained low levels of residual, endogenous virus or had been superinfected with HIV-1 IIIB. The iDC were also directly infected with HIV-1 IIIB. The iDC were then matured with trimeric CD40L (mDC) and used to stimulate interferon gamma (IFN-gamma) production in autologous T cells (quantitation by ELISPOT). Results: CD40L treatment resulted in similar maturation of iDC from both the HIV-1-infected and uninfected persons as shown by increases in expression of surface costimulatory and HLA molecules. Flow cytometry and confocal microscopy indicated that 30-50% of the iDC ingested either the AP or NE cell preparations, compared to only 3-7% by mDC. Treatment with the AP or NE antigen preparations increased expression of HLA DR and CD86 on iDC, but had no consistent change in expression of surface markers on mDC. The iDC loaded with autologous, AP cells and matured with CD40L, induced IFNgamma in PBMC from 4 of the 8 study subjects. Higher levels IFNgamma were induced in PBMC of 7 of the 8 subjects by mDC that had been loaded with HIV-1 IIIB superinfected, AP cells. T cell reactivity to the mDC loaded with the AP preparations was mediated by HLA class I and II restricted, CD8+ and CD4+ T cells. Comparable levels of IFNgamma were induced over 2 years in PBMC from HIV-1-infected subjects by autologous mDC loaded with HIV-1 IIIB superinfected AP cells. In contrast, mDC loaded with HIV-1 IIIB superinfected, NE cells, or directly infected with HIV-1 IIIB alone, did not induce HIV-1-specific T-cell responses. Conclusions: HIV-1-infected AP cells are a potent source of antigen in mDC for recovery of anti-HIV-1 CD8+ and CD4+ T cells from persons on long-term combination antiretroviral therapy. This may be a major pathway for activation of T-cell responses during HIV-1 infection, and could be an approach for enhancement of T-cell reactivity to residual, autologous HIV-1 during combination drug therapy.

©2002 9th Conference on Retroviruses and Opportunistic Infections