The antiviral factor tripartite interaction motif 5α (Trim5α) restricts a broad range of retroviruses in a species-specific manner. Although human Trim5α is unable to block HIV-1 infection in human cells, a modest inhibition of HIV-1 replication has been reported. Recently two polymorphisms in the Trim5 gene (H43Y and R136Q) were shown to affect the antiviral activity of Trim5α in vitro. In this study, participants of the Amsterdam Cohort studies were screened for polymorphisms at amino acid residue 43 and 136 of the Trim5 gene, and the potential effects of these polymorphisms on the clinical course of HIV-1 infection were analyzed. In agreement with the reported decreased antiviral activity of Trim5α that contains a Y at amino acid residue 43 in vitro, an accelerated disease progression was observed for individuals who were homozygous for the 43Y genotype as compared to individuals who were heterozygous or homozygous for the 43H genotype. A protective effect of the 136Q genotype was observed but only after the emergence of CXCR4-using (X4) HIV-1 variants and when a viral load of 104.5 copies per ml plasma was used as an endpoint in survival analysis. Interestingly, naive CD4 T cells, which are selectively targeted by X4 HIV-1, revealed a significantly higher expression of Trim5α than memory CD4 T cells. In addition, we observed that the 136Q allele in combination with the −2GG genotype in the 5′UTR was associated with an accelerated disease progression. Thus, polymorphisms in the Trim5 gene may influence the clinical course of HIV-1 infection also underscoring the antiviral effect of Trim5α on HIV-1 in vivo.

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...