Activating transcription factor 4 (ATF4) is a central factor in the cellular response to multiple stresses, including altered metabolic conditions, anoxia and hypoxia, and redox stress. ATF4 is triggered by endoplasmic reticulum stress and consequent unfolded protein response. This report identifies for the first time ATF4 as a transcription factor upregulated by HIV-1 infection. Upregulation of ATF4 enhances HIV replication, by synergistic interactions with HIV Tat. Moreover, in specific cell lines ATF4 has a direct transactivating potential on the LTR, even in the absence of Tat. We also provide evidence that expression of ATF4 induces HIV reactivation in chronically infected cell lines. These results show for the first time that ATF4 induction might have an important role in HIV replication, and suggest that ATF4 might represent a convergent signaling molecule for different stressors important in regulating the HIV-1 cycle.