Christine A. Kozak, Ph.D.
Chief, Viral Biology Section
Description of Research Program
The Viral Biology Section has a long-standing interest in the identification and characterization of genes that affect susceptibility to mouse leukemia viruses (MLVs) and to MLV-induced disease. The various inbred strains of laboratory mice and wild mouse species differ in their susceptibility to MLVs, and multiple genes are responsible for these differences. We are specifically interested in those genes that inhibit early stages of the viral replicative cycle. For these studies, we use wild mouse species as well as laboratory strains because the common inbred strains were all derived from the same common progenitors and are therefore not representative of the range of genetic diversity within Mus.
Entry Restrictions
Retroviruses enter cells through interaction with specific cell surface receptors. This virus-receptor interaction defines host range, contributes to pathogenesis, and can provide the basis for the evolution of restriction variants that enable natural populations to evade retrovirus infection. Entry can be blocked by mutations in the receptor gene or by host resistance factors that interfere with receptor function. Our active projects have identified the following:
- Four naturally occurring variants of the XPR1 receptor for the pathogenic polytropic and xenotropic MLV host range groups
- Critical amino acids that form the XPR1 receptor determinants and critical sites in the ecotropic MLV envelope responsible for altered host range and receptor-induced formation of multicleated syncytia
- Roles for receptor and virus-linked glycans in host range and cytopathicity
- Endogenous retrovirus insertions at two restriction loci, Rmcf and Rmcf2, which block exogenous virus infection by receptor interference
Post-entry Restrictions
The prototype for factors that interfere with post-entry stages of virus replication is the Fv1 gene, discovered 40 years ago in studies on resistance for Friend MLV and shown to be a co-opted endogenous retrovirus. We have recently determined that Fv1 is present in three of the four Mus subgenera demonstrating that the gene was acquired about seven MYA. Using phylogenetic sequence analysis, we found evidence for positive selection of this gene throughout Mus evolution. We also identified novel restriction alleles and identified specific codons under positive selection. These evolutionarily important codons include two known to contribute to Fv1 resistance in laboratory mice and three codons clustered in an Fv1 segment homologous to the retroviral region known to be involved in capsid multimerization. This suggests that Fv1 inhibition may result from its binding to virus capsids.
Selected Publications
(View list in PubMed.)
Yan Y, Buckler-White A, Wollenberg K, Kozak CA. Origin, antiviral function and evidence for positive selection of the gammaretrovirus restriction gene Fv1 in the genus Mus. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3259-63.
Stocking C, Kozak CA. Murine endogenous retroviruses. Cell Mol Life Sci. 2008 Nov;65(21):3383-98.
Yan Y, Kozak CA. Novel post-entry resistance to AKV ecotropic mouse gammaretroviruses in the African pygmy mouse, Mus minutoides. J Virol. 2008 Jul;82(13):6120-9.
Yan Y, Jung YT, Wu T, Kozak CA. Role of receptor polymorphism and glycosylation in syncytium induction and host range variation of ecotropic mouse gammaretroviruses. Retrovirology. 2008 Jan; 10;5:2.
Yan Y, Knoper RC, Kozak CA. Wild mouse variants of envelope genes of xenotropic/polytropic mouse gammaretroviruses and their XPR1 receptors elucidate receptor determinants of virus entry. J Virol. 2007 Oct;81(19):10550-7.
Wu T, Yan Y, Kozak CA. Rmcf2, a xenotropic provirus in the Asian mouse species Mus castaneus, blocks infection by polytropic mouse gammaretroviruses. J Virol. 2005 Aug;79(15):9677-84.
back to top