A combination of Interferon Stimulated Genes is more effective than IFNα and IFNss in reducing HIV-1 replication in human cervicovaginal tissues

Enhancing antiviral responses while controlling immune cell activation is an attractive strategy to reduce HIV-1 replication in the cervicovaginal mucosae, a primary site of heterosexual transmission. Interferon alpha and beta (IFN/{beta}) signaling up-regulates expression of inflammatory factors and Interferon-Stimulated Genes (ISGs). The simultaneous induction of both IFNs by pathogen-bound molecular pattern recognition receptors and the paucity of data on the anti-HIV-1 efficacy of a combination of these antiviral factors or their downstream targets in human experimental models taking into account mucosal and submucosal cell populations, motivated us to determine whether combined IFN/{beta} or ISGs could decrease HIV-1 replication in cervicovaginal tissues.\n\nIFN/{beta} reduced HIV-1 p24 release. This reduction was associated with upregulation of expression of a subset of ISGs, the type I IFN receptor and interferon regulatory factor seven. IFN/{beta} also enhanced immune cell activation. In contrast, when added directly to CV tissues, a combination of ISGs was more effective than IFN/{beta} in reducing HIV-1 p24 release. The ISG combination demonstrated early kinetics and a more robust reduction in HIV-1 p24 release. Opposite to IFN/{beta}, the combination of ISGs did not induce immune cell activation.\n\nIFN/{beta}-induced ISGs provide novel mucosal therapeutic targets with a greater capacity to reduce HIV-1 compared to IFN/{beta}, without inducing immune cell activation.