Endogenous retroviruses mediate IFN-independent protection against vaginal HSV-2 infection

Abstract Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not known. Here we used herpes simplex virus type 2 (HSV-2) infection and found that mice deficient in Toll-like receptor 7 (Tlr7−/−) that have high systemic levels of infectious ERVs are resistant to intravaginal HSV-2 infection compared with wildtype C57BL/6 (B6) mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7−/− background (Emv2−/−Tlr7−/−) and found that Emv2−/−Tlr7−/− mice are no longer protected against HSV-2. Intravaginal application of purified ERVs prior to HSV-2 infection in both B6 and highly susceptible interferon-alpha receptor-deficient (Ifnar1−/−) mice delayed disease course. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7−/− mice or B6 mice treated with purified ERVs. Instead, we observed enhanced expression of epithelial tight junction protein, E-cadherin, in the vaginal epithelium of ERV-treated B6 mice. Similar increase in tight junction proteins was observed in Tlr7−/− but not in the Emv2−/−Tlr7−/− mice. Together, our results showed that IFN-independent modulation of the vaginal epithelium by ERVs protects mice against vaginal HSV-2 infection and lowers disease burden.