Christine Kozak, Ph.D.

The focus of the Viral Biology Section (VBS) is the genetic basis of resistance to retroviruses. We work largely with mice and the various host range subgroups of the mouse leukemia viruses (MLVs), which are members of the gammaretrovirus genus, although we have expanded our interests to investigate other endogenous retroviral genera in mice as well as in humans and frogs, and we are examining restriction factors active against retroviruses other than MLVs. Our traditional focus on MLVs derives from the fact that inbred strains of laboratory mice and wild mouse species differ in their susceptibility to MLV infection and to virus-induced diseases, and studies using this mouse model system have produced a wealth of information on host resistance factors and the mechanisms by which these viruses induce neoplastic, immunological and neurological diseases. These viruses are also mutagenic agents that can alter host gene expression and genomic architecture, and there is evidence of epizoonotic transmission of rodent gammaretroviruses across multiple species resulting in disease and endogenization into new host species.

We aim to characterize host resistance factors against retroviruses and their viral targets and to elucidate responsible mechanisms. We are currently focused on a new late-acting, broadly anti-retroviral restriction factor that we term ResERV, which has antiviral orthologs in most mammalian species. Other studies on antiviral host factors deal with the previously described host resistance factors Fv1, TRIM5a and BST2/Tetherin. We have recently shown that Fv1, initially described as mouse specific, has a longer evolutionary history with orthologs in multiple rodents that show evidence of a long history of antiviral conflicts. We have also discovered that the antiviral TrimCyp fusion proteins found in primates are also present in various rodents indicating that such antiviral fusion proteins are more widely generated than previously thought.

A second series of projects deals with endogenous retroviruses (ERVs) of mice and other vertebrates. Recent projects include analysis of a human ERV gag gene conserved in primates that has placenta-specific expression and a study on related ERV envelope genes in ungulates and carnivores that are under purifying selection. We also characterized an unusual intact ERV found in Xenopus, recombinant MLVs produced in individual mice during virus-induced pathogenesis and ERV deletion variants that predominantly affect the viral envelope.

A third set of studies focuses on host factors that block entry, specifically the functionally polymorphic host-encoded cell surface receptors. These include CAT1, the receptor for ecotropic MLVs, and XPR1, the receptor for the xenotropic-polytropic MLVs, viruses found in globally distributed wild mice that are infectious for virtually all mammals and birds. This work has identified sequence variations in mammalian species that preserve or limit receptor function and described the coevolutionary trajectories at the interacting sites in receptor and viral envelope across mouse taxa and within geographically separated populations. We are currently working to identify viral envelope sites responsible for receptor interactions, and to define receptor topology and the role of glycosylation, splicing and dimerization in receptor function.