• Zheng Zhang, Xiangsheng Xu, Jiyun Lu, Shuye Zhang, Lanlan Gu, Junliang Fu, Lei Jin, Haiying Li, Min Zhao, Jiyuan Zhang, Hao Wu, Lishan Su, Yang-Xin Fu, and Fu-Sheng Wang.
• Research Center for Biological Therapy, Beijing 302 Hospital, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
• J. Infect. Dis. 2011 Jun 1;203(11):1668-78.

BackgroundNonspecific T-cell hyperactivation is the main driving force for human immunodeficiency virus (HIV)-1 disease progression, but the reasons why the excess immune response is not properly shut off are poorly defined.MethodsEighty-five HIV-1-infected individuals were enrolled to characterize B and T lymphocyte attenuator (BTLA) expression and function. Infection and blockade assays were used to dissect the factors that influenced BTLA signaling in vitro.ResultsBTLA expression on overall CD4(+) and CD8(+) T cells was progressively decreased in HIV-1 infection, which was directly correlated with disease progression and CD4(+) T-cell differentiation and activation. BTLA(+)CD4(+) T cells from HIV-1-infected patients also displayed an altered immune status, which was indicated by reduced expression of naive markers but increased activation and exhaustion markers. Cross-linking of BTLA can substantially decrease CD4(+) T-cell activation in vitro. This responsiveness of CD4(+) T cells to BTLA-mediated inhibitory signaling was further found to be impaired in HIV-1-infected patients. Furthermore, HIV-1 NL4-3 down-regulated BTLA expression on CD4(+) T cells dependent on plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α. Blockade of IFN-α or depletion of pDCs prevents HIV-1-induced BTLA down-regulation.ConclusionsHIV-1 infection potentially impairs BTLA-mediated signaling dependent on pDC-derived IFN-α, which may contribute to broad T-cell hyperactivation induced by chronic HIV-1 infection.

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