Recurrent Loss of APOBEC3H Activity during Primate Evolution

Abstract

Genes in the family encode cytidine deaminases that provide a barrier against viral infection and retrotransposition. Of all genes in humans, () 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. In order to broaden our understanding of A3H-Vif interactions, as well as its evolution in Old World monkeys, we characterized A3H variation within four African green monkey (AGM) subspecies. We found that A3H is highly polymorphic in AGMs and has 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. Moreover, we demonstrate that the evolution of A3H in the primate lineages leading to AGMs was not driven by Vif. Our 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. Adaptation of viruses to their hosts is critical for transmission of viruses between different species. Previous studies had identified changes in a protein from the APOBEC3 family that influenced species-specificity of simian immunodeficiency viruses (SIVs) in African green monkeys. We studied the evolution of a related protein in the same system, APOBEC3H, which has experienced a loss of function in humans. This evolutionary approach revealed that recurrent loss of APOBEC3H activity has taken place during primate evolution suggesting that APOBEC3H places a fitness cost on hosts. The variability of APOBEC3H activity between different primates highlights the differential selective pressures on the gene family.

Variability in Codon Usage in Coronaviruses Is Mainly Driven by Mutational Bias and Selective Constraints on CpG Dinucleotide

“…The evolution of the APOBEC3 locus is tightly linked to viral infections via a different arms race [ 63 , 64 ]. The structure and synteny in the APOBEC3 locus and the protein repertoire therein encoded are extremely lineage-specific (see for instance [ 65 , 66 ] for Chiroptera or [ 67 , 68 ] for Primates). It is thus important to note that the mutagenic role of host APOBEC3 enzymes acting onto viral genomes and exerting strong evolutionary pressures in a particular virus–host interaction may fuel viral adaptations, which facilitate viral transmission and colonisation of novel host species, as suggested for lentiviruses infecting Primates [ 69 ].…”

Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity

“…Interestingly, the loss of A3H activity is not unique to humans, as an evolutionary analysis of A3H in Old World monkeys found that A3H activity has been lost in multiple primate species [43]. Moreover, several residues in the putative RNA binding region of Loop 1 were found to influence the antiviral potency of African green monkey and patas monkey A3H, providing further evidence that mutations introduced in this loop are a recurrent evolutionary mechanism that results in a loss of function [43]. It is unknown why these loss-of-function mutations of A3H arise and become fixed in multiple primate species despite the established importance of this restriction factor in the control of retroviruses.…”

APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1

“…The following day, cells were transfected with 600 ng provirus (HIV-1ΔVifΔEnvLuc2, unless otherwise noted), 100 ng L-VSV-G (vesicular stomatitis virus G), and 400 ng pcDNA4/TO.A3.3XFLAG or pcDNA4/TOPO empty vector unless otherwise indicated. At 72 h later, virus was harvested and normalized for virion production using an RT-qPCR assay, as described previously (41,42). A volume of virus equivalent to 2,000 mU/ml of reverse transcriptase was used for infection of SUPT1 cells.…”