The productive infection of HIV, which generates new viral progeny, depends on the activation status of the cell. In this study, we found cocaine exposure sensitizes partially active CD4+ T cells and makes them poised for productive HIV infection. We discovered that cocaine treatment enhances the metabolic state of the cells by co-stimulating several transcription factors, mainly NFAT and AP-1, the two transcription factors, which specifically play a crucial role in enhancing both HIV and the overall cellular gene expression in T cells. We found that cocaine-induced AP-1 works in tandem with NFAT to boost HIV transcription. The enhanced HIV transcription upon cocaine exposure was further confirmed through higher phosphorylation of the crucial serine residues at the carboxyl-terminal domain (CTD) of RNA polymerase II. The insights gained from this study could aid in developing highly specialized therapeutics combating the deleterious effects of cocaine on the cocaine-using HIV population.Keywords: Molecular biology; Molecular mechanism of gene regulation; Virology; mmunology.