In progressive HIV-1 infection, TIM-3 expression was upregulated on HIV-1-specific CD8 + T cells. TIM-3-expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the TIM-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specific T cells. Here, MAPK3 is linked to HIV-1 infection.