Mycobacterium tuberculosis PE_PGRS62 protein inhibits type I IFN responses to promote HIV-2 replication by directly interacting with IRF3

Co-infection with Mycobacterium tuberculosis (Mtb) and HIV-2 increased the viral load of HIV-2. Type I interferons (IFNs) are essential for limiting HIV-2 progression. However, it is unclear whether and how Mtb affects HIV-2 co-infection by regulating type I IFNs. Here, Mtb PE_PGRS62 protein was identified as an inhibitor of cGAS-STING-mediated type I IFN expression by performing functional screens. Ectopic expression of PE_PGRS62 impaired type I IFN expression stimulated by cytosolic DNA, while knockout of pe_pgrs62 potentiated Mtb-induced type I IFN and downstream IFN-stimulated gene. PE_PGRS62 interacts directly with IRF3 and inhibits the interaction of IRF3 with TBK1 as well as the binding of IRF3 to the IFNβ promoter. Furthermore, reduced HIV viral load was observed in pe_pgrs62 knockout Mtb-infected macrophages compared with wild type Mtb. These findings reveal an important mechanism by which Mtb infection promotes HIV-2 immune evasion.