Ancient loss of APOBEC3H activity in a clade of primates infected with SIV

Thesis (Ph.D.)--University of Washington, 2018Restriction factors are an important component of the innate immune response against primate lentiviruses like human immunodeficiency virus (HIV) and simian immunodeficiency viruses (SIV). While they inhibit various steps of the viral replication cycle, lentiviruses have consequently developed strategies to antagonize this restriction. Studying the co-evolution of host restriction factors and their viral antagonists can reveal mechanisms behind viral adaptation to host species. Furthermore, such study can also allow us to appreciate the utility of encoding a diverse repertoire of restriction factors and observe how these loci have evolved over evolutionary time. Genes in the APOBEC3 family encode cytidine deaminases that can provide a barrier against both retroviruses and retroelements. These enzymes are packaged into budding virions and hypermutate viral genomes upon infection of a new cell. Of all APOBEC3 genes in humans, APOBEC3H (A3H) is the most polymorphic. Some haplotypes encode stable and active A3H proteins, while others are unstable and poorly antiviral. Such variation in human A3H affects interactions with the lentiviral antagonist Vif, which counteracts A3H via proteasomal degradation. While vif can evolve to antagonize stable and active A3H, not all HIV-1 strains encode Vif proteins that are capable of recognizing and degrading A3H. In order to broaden our understanding of A3H-Vif interactions, as well as its evolution in Old World monkeys, I characterized A3H variation within four African green monkey (AGM) subspecies, which are natural hosts of SIV. I found that A3H is highly polymorphic in AGMs and has independently lost antiviral activity in multiple Old World monkeys. This loss of function was partially related to protein expression levels but was also influenced by amino acid mutations in the N-terminus. Lower packaging efficiency was additionally observed in AGM A3H after its divergence from the most recent common ancestor with patas monkeys. Moreover, I demonstrate that the evolution of A3H in the primate lineages leading to AGMs was not driven by Vif. This work suggests that activity of A3H is evolutionarily dynamic and may have a negative effect on host fitness, resulting in its recurrent loss in primates