To examine the molecular mechanisms on how MALAT1 regulates HIV-1 replication, we performed a series of molecular, biochemical and virological experiments and demonstrated that MALAT1 promotes HIV transcription and infection, via its association with PRC2 core component EZH2, thus preventing EZH2 from binding to HIV-1 LTR and disabling PRC2 complex mediated epigenetic silencing of HIV-1 genes. Here, EZH2 is linked to infection.