Stably expressed APOBEC3H forms a barrier for cross-species transmission of simian immunodeficiency virus of chimpanzee to humans

Abstract

APOBEC3s (A3s) are potent restriction factors of human immunodeficiency virus type 1/simian immunodeficiency viruses (HIV-1/SIV), and can repress cross-species transmissions of lentiviruses. HIV-1 originated from a zoonotic infection of SIV of chimpanzee (SIVcpz) to humans. However, the impact of human A3s on the replication of SIVcpz remains unclear. By using novel SIVcpz reporter viruses, we identified that human APOBEC3B (A3B) and APOBEC3H (A3H) haplotype II strongly reduced the infectivity of SIVcpz, because both of them are resistant to SIVcpz Vifs. We further demonstrated that human A3H inhibited SIVcpz by deaminase dependent as well independent mechanisms. In addition, other stably expressed human A3H haplotypes and splice variants showed strong antiviral activity against SIVcpz. Moreover, most SIV and HIV lineage Vif proteins could degrade chimpanzee A3H, but no Vifs from SIVcpz and SIV of gorilla (SIVgor) lineages antagonized human A3H haplotype II. Expression of human A3H hapII in human T cells efficiently blocked the spreading replication of SIVcpz. The spreading replication of SIVcpz was also restricted by stable A3H in human PBMCs. Thus, we speculate that stably expressed human A3H protects humans against the cross-species transmission of SIVcpz and that SIVcpz spillover to humans may have started in individuals that harbor haplotypes of unstable A3H proteins.

How host genetics dictates successful viral zoonosis

“…The virus adapted its vpu gene, which encodes an antagonist of human Tetherin [51,52]. Similarly, human APOBEC3H drove adaptive change in the viral vif gene encoding the antagonist for APOBEC3 proteins [53]. We don't know whether these vif adaptations were required before the first human infection or afterwards as the virus refined itself for spread in the human population.…”

“…This is because many people, including many Africans, encode APOBEC3H alleles that do not express high levels of protein [43]. It's possible that these individuals provided a lower adaptive barrier for SIVcpz, giving the virus a foothold in the human population and a chance for the resulting HIV to acquire changes in vif that subsequently enabled it to infect more humans [43,53]. In the transmission of SIVcpz to humans, there was a third key adaptive event in SIV matrix protein, although the host factor driving this adaptation remains unknown [54].…”

Recurrent Loss of APOBEC3H Activity during Primate Evolution

“…Indeed, we found that multiple sites in A3H are under positive selection in primates, which is suggestive of an evolutionary arms race between A3H and another protein. Evidence of A3H-Vif interactions are evident in hominoids, as SIVcpz Vif adaptation to stable human A3H was crucial for transmission of SIVcpz (11) to humans and HIV-1 Vif is highly variable in its ability to target stable human A3H proteins (17, 21–23). Interactions between Vif and other A3 proteins have also been well-characterized in chimpanzees and humans (7, 35, 36).…”

“…However, lentiviruses have evolved a mechanism to evade A3 restriction by encoding a viral antagonist, Vif, which binds and targets A3 proteins for proteasomal degradation via a cellular E3 ubiquitin ligase complex (6). Given that A3-Vif interactions often act in a species-specific manner, adaptation of Vif to host A3 proteins is important for successful adaptation of lentiviruses to their hosts (7–11).…”

“…This suggests that there is selection in vivo for Vif strains that counteract the stably expressed forms of A3H in infected people (22, 24, 25). Furthermore, the cross-species transmissions that led to adaptation of SIV from monkeys to chimpanzees to humans, giving rise to HIV-1, involved adaptation of Vif to antagonize the A3 proteins found in each host (7, 8, 10, 11) including adaptation of Vif from SIVcpz to antagonize human A3H (11).…”