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 Fv1nr/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.
Highlights
The innate arm of the immune system could critically shape the adaptive immune response against pathogens
These analyses revealed that 129P2 mice lacked this Xenotropic Murine Leukemia Virus Long Terminal Repeat (X-MLV) LTR insertion in Apobec3 (Fig. 1B), similar to Rfv3s/s BALB and A.BY mice
The Friend retrovirus (FV) infection model was instrumental in the identification of host genes that can influence the retrovirusspecific immune response
Summary
The innate arm of the immune system could critically shape the adaptive immune response against pathogens. Major efforts to understand these innate immune mechanisms against HIV-1 resulted in the identification of restriction factors such as TRIM5a [1] and APOBEC3G [2], but how these factors shape adaptive immune responses against HIV-1 is difficult to study in humans in vivo. The interplay between innate and adaptive immunity has been studied extensively in the Friend retrovirus (FV) infection model [3,4,5]. Fv1 and Rfv are the functional counterparts of human TRIM5a and APOBEC3G, respectively [6,7,8]. Understanding the impact of Fv1 and mouse Apobec (or mA3) on FV adaptive immunity may provide insights for basic HIV vaccine discovery
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