Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 203, Issue 11, Pages 1668-1678Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jir165
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Funding
- National Natural Science Foundation of China [30801040]
- National Key Basic Research Program of China [2006CB504205]
- National Grand Program on Key Infectious Disease [2008ZX10001-002, 2008ZX10001-006, 2009ZX10005-017]
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Background. Nonspecific 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. Methods. Eighty-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. Results. BTLA 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)-alpha. Blockade of IFN-alpha or depletion of pDCs prevents HIV-1-induced BTLA down-regulation. Conclusions. HIV-1 infection potentially impairs BTLA-mediated signaling dependent on pDC-derived IFN-alpha, which may contribute to broad T-cell hyperactivation induced by chronic HIV-1 infection.
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