title: Fv1 restriction and retrovirus vaccine immunity in Apobec3-deficient 129P2 mice.
abstract: Understanding the host genetics of the immune response in retrovirus infection models could provide insights for basic HIV vaccine discovery. In Friend retrovirus (FV) infection of mice, Fv1 differentially inhibits N-tropic versus B-tropic FV infection by mediating a capsid-dependent post-entry block, Fv2 susceptibility governs splenomegaly induction, and Rfv3 resistance primes a stronger neutralizing antibody response due to more potent Apobec3 activity. Apobec3 polymorphisms in inbred mouse strains correlate with Rfv3 resistance and susceptibility, with one unresolved exception. The 129/OlaHsd (129P2) mouse strain is Fv2 and Rfv3 susceptible based on genotyping, but infection of 129P2 mice with B-tropic FV resulted in strong neutralizing antibody responses and no splenomegaly. Here we confirm that 129P2 mice are Fv1(nr/nr), explaining its resistance to B-tropic FV. Infection of 129P2 mice with NB-tropic FV, which can efficiently infect mice independent of Fv1 genotype, resulted in severe splenomegaly, high levels of viremia and weak neutralizing antibody responses regardless of Apobec3 status. Notably, high-dose B-tropic FV infection of 129P2 Apobec3-deficient mice induced significant adaptive immune responses and conferred high levels of protection following challenge with pathogenic NB-tropic FV. This immunological protection complemented previous studies that N-tropic FV can act as a live-attenuated vaccine in Fv1 (b/b) mice. Altogether, the results obtained in 129P2 mice strengthen the conclusion that Rfv3 is encoded by Apobec3, and highlight Fv1 incompatibility as a retroviral vaccine paradigm in mice. Due to its susceptibility to disease that allows for pathogenic challenge studies, B-tropic FV infection of 129P2 mice may be a useful model to study the immunological pathways induced by retroviral capsid restriction.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Kalani
authors.initials: K
authors.lastname: Halemano
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Barrett
authors.forename: Sam X
authors.initials: SX
authors.lastname: Li
authors.forename: Michael S
authors.initials: MS
authors.lastname: Harper
authors.forename: Diana S
authors.initials: DS
authors.lastname: Smith
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Heilman
authors.forename: Mario L
authors.initials: ML
authors.lastname: Santiago
mesh_terms: D000818:Animals; D002460:Cell Line; D003564:Cytidine Deaminase / Q000172:deficiency*; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012192:Retroviridae Infections / Q000276:immunology
chemical_list: C103189:Fv1 protein, mouse; D011506:Proteins; C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase