The ancient and recurrent evolution of Apobec3 antiviral activity in primates

Abstract

Host restriction factors are potent, widely expressed, intracellular blocks to viral replication that are an important component of the innate immune response to viral infection. However, viruses have evolved mechanisms of antagonizing restriction factors. Through evolutionary pressure for both host survival and virus replication, an evolutionary arms race has developed that drives continuous rounds of selection for beneficial mutations in restriction factor genes and their viral antagonists. Because viruses can evolve faster than their hosts, the modern-day vertebrate innate immune system is optimized, for the most part, to defend against ancient viruses, rather than current viral threats. Thus, the evolutionary history of restriction factors might, in part, explain why humans are susceptible or resistant to the viruses present in the modern world. In primates, the Apobec3 family of host restriction factors is a group of seven cytidine deaminases that inhibit the replication of retroviruses and retrotransposons. Here, I characterize the antiviral activity of Apobec3DE across primate species and of Apobec3 family members across human populations. First, I show that human and chimpanzee orthologues of Apobec3DE inhibit retrotransposons that are currently active in hominids. Chimpanzee Apobec3DE also potently restricts lentiviruses, unlike human Apobec3DE, which has weaker antiviral activity against retroviruses. I also show that Apobec3DE evolved rapidly in chimpanzee ancestors, and this ancient evolution drove the increased antiviral activity of chimpanzee Apobec3DE against modern-day viruses. Next, I evaluate novel variants of Apobec3 genes in diverse human populations. I show that polymorphisms in Apobec3DE, Apobec3F, and Apobec3G decrease endogenous expression or antiviral activity against HIV-1. Interestingly, I find that Apobec3DE has evolved under purifying selection in humans, suggesting that mutations in Apobec3DE may be weakly deleterious. However, because the current level of Apobec3DE antiviral activity against HIV-1 is not optimal, Apobec3DE likely evolved to recognize an ancient virus unlike HIV-1. Together, this data suggests that Apobec3DE is likely to play a role in host defense against retroelements in primates and may alter our susceptibility to viruses.