Human APOBEC3G Prevents Emergence of Infectious Endogenous Retrovirus in Mice

Abstract

Endogenous retroviruses (ERV) are found throughout vertebrate genomes, and failure to silence their activation can have deleterious consequences on the host. Mutation and subsequent disruption of ERV loci is therefore an indispensable component of the cell-intrinsic defenses that maintain the integrity of the host genome. Abundant in vitro and in silico evidence have revealed that APOBEC3 cytidine-deaminases, including human APOBEC3G (hA3G), can potently restrict retrotransposition; yet, in vivo data demonstrating such activity is lacking, since no replication-competent human ERV have been identified. In mice deficient for Toll-like receptor 7 (TLR7), transcribed ERV loci can recombine and generate infectious ERV. In this study, we show that ectopic expression of hA3G can prevent the emergence of replication-competent, infectious ERV in Tlr7−/− mice. Mice encode one copy of Apobec3 in their genome. ERV reactivation in Tlr7−/− mice was comparable in the presence or absence of Apobec3. In contrast, expression of a human APOBEC3G transgene abrogated emergence of infectious ERV in the Tlr7−/− background. No ERV RNA was detected in the plasma of hA3G+ Apobec3−/− Tlr7−/− mice, and infectious ERV virions could not be amplified through coculture with permissive cells. These data reveal that hA3G can potently restrict active ERV in vivo and suggest that expansion of the APOBEC3 locus in primates may have helped to provide for the continued restraint of ERV in the human genome. IMPORTANCE Although APOBEC3 proteins are known to be important antiviral restriction factors in both mice and humans, their roles in the restriction of endogenous retroviruses (ERV) have been limited to in vitro studies. Here, we report that human APOBEC3G expressed as a transgene in mice prevents the emergence of infectious ERV from endogenous loci. This study reveals that APOBEC3G can powerfully restrict active retrotransposons in vivo and demonstrates how transgenic mice can be used to investigate host mechanisms that inhibit retrotransposons and reinforce genomic integrity.

Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice

“…Bumble mice (B6 background) were obtained from Mutant Mouse Resources & Research Centers supported by NIH (MMRRC). Tlr7 Ϫ/Ϫ mice (B6 background) and Ifnar1 Ϫ/Ϫ mice (B6 background) were from Akiko Iwasaki and Priti Kumar, Yale University (50). IL-10 Ϫ/Ϫ mice (B6 background) were from Jorge Galán and Ruslan Medzhitov, Yale University.…”

Retroviruses drive the rapid evolution of mammalianAPOBEC3genes

“…To combat ERVs and other intragenomic parasites, mammals have developed defense systems such as Krüppel-associated box domain-containing (KRAB) zinc finger proteins (17) and PIWI-interacting RNAs (18). A3 proteins have been shown to suppress the replication of reconstructed ERVs in cell cultures (15,19) and in a transgenic mouse model (20). Furthermore, previous studies identified the signature of A3-mediated G-to-A mutations in ERVs indicating that ancient retroviruses experience attacks by A3 proteins (15,16,19,21).…”

Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

“…The single copy of mA3 is also under positive selection in Mus, and the positively selected residues in the catalytically active A3Z2 domain line the substrate groove that accommodates nucleic acids [ 160 ]. The demonstration that A3 proteins can also more broadly restrict replication of endogenous retroviruses and retrotransposons, indicate that A3 mutators have been in conflict with retroelements throughout mammalian evolution [ 175 , 176 , 177 , 178 , 179 ]. Furthermore, A3G has been demonstrated to have broader antiviral activity that can block HBV, replication of which includes a reverse transcription step [ 180 , 181 , 182 ].…”