Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

We previously observed a loss of EpsteinBarr virus (EBV)-specific CD8 ؉ T cells in subjects progressing to EBV-related nonHodgkin 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 ␥ (IFN␥) production, directed against a latent (EpsteinBarr 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-EBVrelated disease and slow progressors. Loss of EBNA1-specific T-cell immunity IntroductionThe Epstein-Barr virus (EBV) is a widespread human ␥-herpesvirus that persists for life in resting memory B cells after primary infection in the oropharynx. 1,2 Both primary infection as well as subsequent reactivations of the virus and proliferation of EBV-infected B cells are controlled mainly by CD8 ϩ T cells. 3,4 In immunosuppressed individuals a combination of factors may lead to lymphoproliferative disorders. 5,6 In HIV-infected subjects the risk of non-Hodgkin lymphoma (NHL) is 60-to 100-fold increased compared with the general population. [7][8][9] Most of these lymphomas are large B-cell lymphomas of which 50% to 70% are EBV positive. 10,11 While in HIV-infected individuals EBV-specific CD8 ϩ T cells are generally well preserved, 12,13 their ability to secrete interferon ␥ (IFN␥) in short-term antigen-specific stimulation assays is decreased, and in individuals progressing toward AIDS-related non-Hodgkin lymphoma the CD8 ϩ T-cell function ultimately collapses completely. 14 An association of this loss of CD8 ϩ T-cell function with a decrease in total CD4 ϩ T-cell numbers 14 suggests that a lack of EBV-specific CD4 ϩ T-cell help could play a role in disease progression. This would be in accordance with many human [15][16][17][18][19] and animal studies [20][21][22][23][24][25][26] that demonstrate the importance of CD4 ϩ T cells in the development and maintenance of effective CD8 ϩ T-cell responses.While the importance of EBV-specific CD8 ϩ T cells has been clearly demonstrated, and both the height and patterns of immunodominance of these CD8 ϩ T-cell responses are clearly defined, to date few data on EBV-specific CD4 ϩ T-cell responses are available. Due to the extremely low frequencies of these cells, only few investigators have been able to determine the ex vivo magnitude of the EBV-specific CD4 ϩ T-cell response. 27...