The recognition of microbial patterns by Toll-like receptors (TLRs) is critical for activation of the innate immune system. Although TLRs are expressed by human CD4(+) T cells, their function is not well understood. Here we found that engagement of TLR7 in CD4(+) T cells induced intracellular calcium flux with activation of an anergic gene-expression program dependent on the transcription factor NFATc2, as well as unresponsiveness of T cells. As chronic infection with RNA viruses such as human immunodeficiency virus type 1 (HIV-1) induces profound dysfunction of CD4(+) T cells, we investigated the role of TLR7-induced anergy in HIV-1 infection. Silencing of TLR7 markedly decreased the frequency of HIV-1-infected CD4(+) T cells and restored the responsiveness of those HIV-1(+) CD4(+) T cells. Our results elucidate a previously unknown function for microbial pattern-recognition receptors in the downregulation of immune responses.