Differential Activity of APOBEC3F, APOBEC3G, and APOBEC3H in the Restriction of HIV-2

Human immunodeficiency virus (HIV) mutagenesis is driven by a variety of internal and external sources, including the host APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypetide-like 3; A3) family of restriction factors, which catalyze G-to-A transition mutations during virus replication. HIV-2 replication is characterized by a relative lack of G-to-A mutations, suggesting infrequent restriction by A3 proteins. To date, the activity of the A3 repertoire against HIV-2 has remained largely uncharacterized, and the mutagenic activity of these proteins against HIV-2 remains to be elucidated. In this study, we provide the first comprehensive characterization of the restrictive capacity of A3 proteins against HIV-2 in cell culture using a dual fluorescent reporter HIV-2 vector virus. We found that A3F, A3G, and A3H restricted HIV-2 infectivity in the absence of Vif and were associated with significant increases in the frequency of viral mutants. These proteins increased the frequency of G-to-A mutations within the proviruses of infected cells as well. A3G and A3H also reduced HIV-2 infectivity via inhibition of reverse transcription and the accumulation of DNA products during replication. In contrast, A3D, did not exhibit any restrictive activity against HIV-2, even at higher expression levels. Taken together, these results provide evidence that A3F, A3G, and A3H, but not A3D, are capable of HIV-2 restriction. Differences in A3-mediated restriction of HIV-1 and HIV-2 may serve to provide new insights in the observed mutation profiles of these viruses.