microRNA-422a promotes HIV replication and innate immune evasion by targeting MECP2

in people living with HIV (PLWH), and the extent of miR-422a reduction was correlated with viral load reduction. Here, we investigated the molecular basis of this relationship by examining the role of miR-422a in HIV replication and innate immune evasion. We observed that HIV-1 infection induces miR-422a expression in primary CD4+ T cells via the viral Nef accessory protein. miR-422a enhanced HIV-1 replication in CD4+ T cells by directly targeting the host factor methyl CpG binding protein 2 (MECP2). Transcriptomic analysis revealed that miR-422a depletion mimicked IFNα exposure, inducing the expression of several IFN-stimulated genes (ISGs) that restrict HIV-1 replication. Finally, we demonstrated that miR-422a overexpression or CRISPR-Cas9-mediated MECP2 knockout counteracts IFNα antiviral capacity and rescues HIV-1 replication. Together, our findings reveal that miR-422a is a key host factor induced by HIV-1 infection that supports viral replication and subverts type I IFN-mediated antiviral responses via targeting of MECP2. Virologic control in PLWH may be achieved by pharmacologic manipulation of the Nef-miR-422a-IFNα axis.