Endogenous Ecotropic Murine Leukemia Virus Promotes Prion Pathogenesis in Senescence-accelerated Mice

Among senescence-accelerated prone mice (SAMP), the SAMP8 and SAMP10 strains exhibit significant age-related deteriorations in learning and memory. Previous studies have reported that SAMP strains carry high level of Akv-type endogenous ecotropic murine leukemia virus (E-MuLV), whereas the senescence-accelerated resistant strain SAMR1 contains very low or undetectable levels of the virus. Retroviral infections, including MuLV, have been implicated in the acceleration of prion pathogenesis. Prion diseases are characterized by neuronal loss, spongiform degeneration, and astrogliosis and are caused by the infectious prion protein (PrP^Sc), which arises from the misfolding of the normal cellular prion protein (PrP^C). Notably SAMP8 mice infected with scrapie exhibit shortened survival and increased PrP^Sc accumulation compared with SAMR1 mice. In this study, we investigated the role of endogenous E-MuLV to prion disease progression using senescence-accelerated mouse models. Following infection with the 22L scrapie strain, SAMP10 mice displayed significantly shortened survival compared with SAMR1 mice after both intracerebral (IC: 121.8±1.3 vs. 141.0±2.2 days) and intraperitoneal (IP: 184.4±1.3 vs. 216.2±2.7 days) inoculation. SAMP10 mice also showed earlier and more pronounced PrP^Sc accumulation during the clinical phase, along with enhanced vacuolation. Furthermore, in a cerebellar slice culture model of 22L scrapie infection, treatment with the antiretroviral drug zidovudine significantly reduced PrP^Sc accumulation in SAMP10 mice. Taken together, these findings suggest that endogenous E-MuLV contribute to the accelerated prion pathogenesis by promoting early and elevated PrP^Sc accumulation, leading to shortened survival.