The Role of the Antiviral APOBEC3 Gene Family in Protecting Chimpanzees against Lentiviruses from Monkeys

Abstract

Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee’s main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4+ T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey lentiviruses.

The APOBEC Protein Family: United by Structure, Divergent in Function

“…The duplication and divergence of A3 genes leading to expression of seven major homologs in humans (Figure 1A) may have both been driven by and contributed to mutations that promoted the evolution of endogenous and exogenous retroviruses/retroelements that bind to A3 proteins as substrates for editing [Text box 3] [39–42]. In this regard, the primate A3 subfamily of proteins has distinct but fairly lax nucleotide sequence preferences adjacent to edited Cs (Table 1) that may have been selected by A3 interactions that better controlled invasion by diverse retroviruses.…”

How host genetics dictates successful viral zoonosis

“…The SIV/HIV protein Vif neutralizes APOBEC3 proteins in host cells. SIV from monkeys could not neutralize chimpanzee APOBEC3D and APOBEC3G proteins, and so the vial vif gene had to adapt before or during this transmission event [49]. A second host protein, RanBP2, also drove viral adaptation during this transmission event.…”

Primate immunodeficiency virus classification and nomenclature: Review

“…The SIV lineage infecting chimanzees and gorillas is apparently the result of a very ancient recombination event, with the pol gene of SIVcpz somewhat related to virus from red capped mangabeys while the env gene is more closely related to virus from greater spot-nosed monkeys(Etienne et al, 2013)(Bailes, 2003) (Leitner et al, 2007). Fighting and predation between primate species is rather common, so the relative lack of cross species transmission events is a testament to how well the primate APOBEC system, and other innate and adaptive immune functions protect against these viruses(Puvvada and Patel, 2013)(Bibollet-Ruche et al, 2004)(Etienne et al, 2015)(D’arc et al, 2015). …”