Genetic Aspects Of Viral Oncogenesis In Inbred Strains and Wild Mouse Species

National Institute Of Allergy And Infectious Diseases

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Abstract

Our work has long focused on mouse leukemia viruses (MLVs), some of which are pathogenic, the various host factors that restrict the replication of these viruses, and the adaptive co-evolution of interactive host/pathogen pairings. This work examines laboratory mouse strains as well as wild mice for a broad sampling of the genetic diversity in Mus and to examine survival strategies in natural populations that harbor virus and in geographically separated species. The wild mice additionally provide a source of novel resistance genes and virus variants. In FY21, we expanded these studies to describe unusual and functionally important ERVs found in humans and African frogs. In FY21, we identified a provirus, HERV-V1, that contains the oldest primate gag gene with an ORF, an intact env and the first ORF in an HERV gag leader. HERV-V1 is linked to a related gag gene, and these genes are all evolutionarily conserved in simian primates with an age of 43 million years. The two gag genes have undergone recurrent gene conversion events and positive selection and their expression is restricted to the placenta in humans and macaques suggesting co-option for placenta-specific host functions. Transcriptomic analysis of human tumors also found upregulated gag levels in diffuse large B-cell lymphomas and may be useful markers for this lymphoma. These conserved gag genes may have contributed to the successive domestications of env and gag genes in eutherians involved in the ongoing ERV-driven evolution of the placenta. In FY21, we found an unusual endogenous retrovirus, XtERV-S, in Xenopus tropicalis. This ERV has intact open reading frames for all viral proteins, but has an unusual genomic structure and domain relationships to known retroviruses. The gag and pol genes show closest similarity to the ancient envelope (env)-deficient ERV-L family of endogenous retroviruses, and its acquired env is related to a subgroup of gammaretrovirus env genes with a heptad stutter in the transmembrane subunit. The presence of intact ORFs and identical 5' and 3' LTRs indicate a very recent germline acquisition, although much older related ERVs are found in other African frog taxa. This newly acquired retrovirus thus represents an unusual recombinant that spans retroviral genera. Mice differ in their susceptibility to mouse gammaretrovirus infection and to virus-induced diseases, and the responsible genes are generally shared by other mammalian species. In FY21, we investigated the MLV cell surface receptors CAT1 and XPR1, and the post-entry restriction factor Fv1. MLVs evolved in concert with restrictive host factors with some under positive selection, including the XPR1 receptor for xenotropic/polytropic MLVs (X/P-MLVs) and the post-entry restriction factor Fv1. Since positive selection marks host-pathogen genetic conflicts, we examined MLVs for counter-adaptations at sites that interact with XPR1, Fv1 and the CAT1 receptor for ecotropic MLVs (E-MLVs). Results describe different co-adaptive evolutionary paths within the ranges occupied by these virus-infected subspecies. The interface of CAT1 and the otherwise variable E-MLV envelopes is highly conserved; antiviral protection is afforded by the Fv4 restriction factor. XPR1 and X/P-MLVs variants show coordinate geographic distributions with receptor critical sites in envelope under positive selection, while mice carrying P-ERVs show little variation in envelope and XPR1. The major Fv1 target in the viral capsid is under positive selection, and the distribution of Fv1 alleles is subspecies-correlated. These data document adaptive spatial and temporal co-evolutionary trajectories at the critical interfaces of MLVs and the host factors that restrict their replication.