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Session 10 Oral Abstract Session Late Breakers I Session Time: Monday, 2 pm - 4 pm Room 6E

3:30   LB7. HIV Preferentially Infects HIV-Specific CD4 T Cells D. Douek*1, J. Brenchley1, M. Betts1, D. Ambrozak1, B. Hill1, Y. Okamoto1, J. Casazza2, J. Kuruppu1, K. Kunstman3, M. Dybul1, A. Oxenius4, D. Price4, M. Connors1, and R. Koup1 1NIAID, NIH, Bethesda, MD; 2Univ. of Texas Southwestern Med. Ctr., Dallas; 3Northwestern Univ. Med. Sch., Chicago, IL; and 4John Radcliffe Hosp., Oxford, UK Background: HIV infection is associated with the progressive loss of CD4 T-cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4 T cells are preferentially affected. Methods: We examined 12 viremic HIV-infected subjects, and 4 subjects before and after structured therapy interruption (STI). We FACS-sorted HIV-specific and CMV-specific memory CD4 T cells by antigen-induced interferon-? production, and also unstimulated bulk CD4+CD45RO+ memory T cells. Using qPCR we measured pro-viral HIV DNA as a quantitative record of infection history. We also measured p24 production as a function of cell division within activated infected naïve and memory T cells. Results: HIV-specific memory CD4 T cells in infected subjects contained more HIV pro-viral DNA than other memory CD4 T cells, at all stages of HIV disease. Such preferential infection of HIV-specific naïve T cells might occur during acute HIV infection, and indeed we found that activated naïve CD4 T cells are exquisitely sensitive to infection. Following viral rebound during STI, the frequency of HIV pro-viral DNA in the HIV-specific memory CD4 T-cell pool increases to a greater extent than in memory CD4 T-cells of other specificities. The increase is directly proportional to the frequency of pro-viral DNA before STI, indicating that the infected memory T cell pool contributes to overall viral replication. Their preferential infection notwithstanding, the vast majority of demonstratively antigen-responsive HIV-specific CD4 T-cells remain virus-free at any time. Conclusions: Our results provide direct evidence that HIV-specific CD4 T cells are preferentially infected in vivo. The loss of HIV-specific CD4 T-cell responses may begin during acute infection, and continue throughout its course, eventually leading to uncontrolled viral replication and AIDS. Whether such progressive loss indeed occurs has yet to be fully established. This preferential but low frequency infection of HIV-specific and other activated T cells may represent an exquisite evolutionary adaptation that enables persistent infection in an otherwise immunocompetent host, and prolonged host-parasite coexistence. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of STI.

©2002 9th Conference on Retroviruses and Opportunistic Infections