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 emergence, an evolutionary “arms race” has developed that drives continuous rounds of selection for beneficial mutations in restriction factor genes. Because viruses can evolve faster than their hosts, the modern-day vertebrate innate immune system is optimized to defend against ancient, extinct viruses, rather than our modern viral threats. Thus, the evolutionary history of restriction factors might, in part, explain why humans are susceptible or resistant to the viruses that are currently circulating. Our evolutionary studies are done in collaboration with the Malik lab.
Many primates in Africa are infected with lentiviruses. HIV-1 arose from cross-species transmissions of SIV in chimpanzees (SIVcpz) to humans 4 times in the last century, and HIV-2 arose from cross-species transmissions of SIV in sooty mangabies (SIVsmm) over 7 times. We are interested in determining the factors that influence adaptation of viruses to humans, and in what factors may protect humans from infection from additional species.
Within the past century, a number of “emerging viruses” with pathogenic properties have entered the human population on a large scale. However, novel pathogenic viral infections of humans are not unique to modern history. "Paleovirology" is the study of ancient extinct viruses (called “paleoviruses”) and the effects that these agents have had on the evolution of their hosts. Thus far, the study of these viruses has mostly been limited to endogenous retroviruses that can be directly identified from their remnants in host genomes. However, one can infer the existence of other paleoviruses from their evolutionary pressures on host genes. Our lab looks for such signs of paleoviruses in order to determine the consequences of these ancient viruses on current human susceptibility or resistance to viral pathogens such as HIV.
Ancient infections by pathogenic viruses select for variants in antiviral genes that escape from viral antagonists. Viruses then adapt to these polymorphisms and the cycle continues to our modern day. We have studied the evolution and function of Trim5, SAMHD1, APOBEC3DE, APOBEC3G, APOBEC3H, Tetherin, Viperin, and others.
1. Adaptation of lentiviruses to hominids: We showed that the precursor to HIV-1, SIV from chimpanzees (SIVcpz), underwent a gene deletion event that removed the vpx gene. The result of this deletion is the virus lost the ability to degrade the restriction factor SAMHD1. However, the selective advantage to the deletion is that the vif gene obtained a new C-terminus that allowed it to adapt to counteract the homind version of the restriction factors APOBEC3G and APOBEC3D. Abstract.
2. Human polymorphisms in the antiviral APOBEC3 genes: We identified all high-frequency human polymorphisms in the APOBEC3 locus from the 1000 genome project, and showed that most of them had no effect on antiviral functions. Moreover, we showed that the APOBEC3D gene of humans, which is poorly, active against HIV, has been selected in recent human evolution, likely for its role in protecting the genome from retrotransposition. Abstract.
3. Evolutionary toggling of Vpr/Vpx specificity: The Vpx protein of some lentiviruses and the Vpr protein of other lentiviruses antagonizes the antiviral gene SAMHD1 by causing it to be degraded. We showed that during the evolution of primate lentiviruses, Vpr/Vpx has toggled between using the N-terminus and using the C-terminus of SAMHD1. Text.
4. Selection for SAMHD1 degradation: We used an evolutionary analysis to show that antagonism of SAMHD1 by Vpx is actively selected in populations of monkeys naturally infected wtih SIV. Abstract.
5. Age of Primate Lentiviruses: We showed that the APOBE3G:Vif "arms race" is at least 5 million years old in simian primates, which implies that a pathogenic lentivirus has been present in primates for at leas that long. Text.