Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-hodgkin lymphoma

We previously observed a loss of Epstein-Barr virus (EBV)-specific CD8(+) T cells in subjects progressing to EBV-related non-Hodgkin lymphoma (NHL), correlating with loss of CD4(+) T cells. The aim of the present study was to determine the role of EBV-specific CD4(+) T cells in the development of NHL during chronic HIV infection. To this end, CD4(+) and CD8(+) memory T cells, capable of both proliferation and subsequent interferon gamma (IFN-gamma) production, directed against a latent (Epstein-Barr virus nuclear antigen 1 [EBNA1]) and a lytic (BamH fragment Z left frame 1 [BZLF1]) EBV antigen were studied longitudinally in 9 progressors to NHL, 4 progressors to non-EBV-related AIDS, and 4 slow progressors to AIDS. In all 3 groups we observed a decline of EBV-specific memory CD4(+) and CD8(+) T-cell responses during HIV infection. However, whereas latent antigen EBNA1-specific CD4(+) T cells were lost well before diagnosis in all subjects who developed an AIDS-related NHL (and EBNA1-specific CD8(+) T cells were significantly lower compared with the other groups), these cells were better preserved in progressors to non-EBV-related disease and slow progressors. Loss of EBNA1-specific T-cell immunity thus might be important for progression to NHL. Interestingly, BZLF1-specific T cells were not lost in all progressors to NHL, suggesting a different function of these cells in the surveillance of EBV-infected B cells.