AIDS Vaccine 2001 Conference Session

30 Functional Impairment of EBV- and HIV-Specific CD8⁺ T Cells in HIV Infection: CD27 Provides a Clue

D. van Baarle*, S. Kostense, E. Hovenkamp, J. Joling, N. Dukers, M. van Oers, and F. Miedema
CLB Sanquin and Univ. of Amsterdam, The Netherlands

To investigate why progression to AIDS occurs despite high numbers of virus-specific CD8⁺ T cells, we studied number (using HLA-tetrameric complexes), function (using IFNgamma elispot assays), and phenotype (as determined by CD27 and CD45RO expression) of both HIV- and Epstein-Barr virus (EBV)-specific CD8⁺ T cells in the course of HIV infection. During progression to AIDS, HIV-specific IFNgamma⁺ CD8⁺ T cells consistently declined. The loss of IFNgamma⁺ T cells correlated with declining CD4⁺ T-cell counts. In addition, HIV-specific T cells were consistently of the CD27⁺ memory phenotype. Individuals with relatively high numbers of CD27⁽ effector T cells showed delayed progression to AIDS. These data indicate that antiviral activity is not lost by physical depletion of HIV-specific CD8⁺ T cells, but by a block in effector differentiation and a reduction in antigen responsiveness per cell. In addition we studied EBV-specific T cells, which are important in controlling EBV, a widespread human gamma herpesvirus that may cause AIDS-related non-Hodgkin’s Lymphomas (AIDS-NHL). We observed in AIDS-NHL patients that during the course of HIV-infection, EBV-specific CD8⁺ T cells did not disappear but rather lost their capability to produce IFNgamma. This loss of function of EBV-specific CD8⁺ T cells correlated with lower CD4⁺ T-cell numbers and was characterized by preservation of the CD27⁺ memory phenotype. In long-term asymptomatic individuals, in whom CD4⁺ T-cell numbers were maintained and EBV-specific T cells differentiated into the CD27⁽ phenotype, IFNgamma-producing EBV-specific T cells were stable. Interestingly, HIV-infected individuals in whom EBV-specific T cells do differentiate into CD27⁽ CD8⁺ T cells appeared to be protected from development of AIDS-NHL. We conclude that differentiation into CD27⁽ CD8⁺ T cells is essential in controlling chronic virus infections, and we propose a model in which CD4⁺ T-cell help is crucial either to establish efficient differentiation into CD27⁽ T cells or to maintain CD27⁽ T cells. Since we show that these CD27⁽ T cells have a higher functional capacity, they are important effector T cells to delay or prevent disease progression in HIV infection.

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