In this study, Tsai et al. set out to study how cellular m 6 A recognition proteins regulate HIV gene expression. Using genetic and genomic approaches, the authors report that m 6 A regulates HIV gene expression by at least two distinct mechanisms. First, m 6 A assures the optimal alternative splicing of HIV-1 transcripts by recruiting the nuclear m 6 A reader YTHDC1. Second, while they confirm previous reports that m 6 A can destabilize cellular mRNAs via recruitment of the cytoplasmic m 6 A reader YTHDF2, they found that YTHDF2 binding to m 6 A sites on HIV-1 transcripts instead enhances the stability of these viral mRNAs. Previous work has demonstrated that the epitranscriptomic addition of m 6 A to viral transcripts can promote the replication and pathogenicity of a wide range of DNA and RNA viruses, including HIV-1, yet the underlying mechanisms responsible for this effect have remained unclear. It is known that m 6 A function is largely mediated by cellular m 6 A binding proteins or readers, yet how these regulate viral gene expression in general, and HIV-1 gene expression in particular, has been controversial. Here, we confirm that m 6 A addition indeed regulates HIV-1 RNA expression and demonstrate that this effect is largely mediated by the nuclear m 6 A reader YTHDC1 and the cytoplasmic m 6 A reader YTHDF2. Both YTHDC1 and YTHDF2 bind to multiple distinct and overlapping sites on the HIV-1 RNA genome, with YTHDC1 recruitment serving to regulate the alternative splicing of HIV-1 RNAs. Unexpectedly, while YTHDF2 binding to m 6 A residues present on cellular mRNAs resulted in their destabilization as previously reported, YTHDF2 binding to m 6 A sites on HIV-1 transcripts resulted in a marked increase in the stability of these viral RNAs. Thus, YTHDF2 binding can exert diametrically opposite effects on RNA stability, depending on RNA sequence context.