Date Published: October 12, 2016
Publisher: Public Library of Science
Author(s): Cristina J. Wittkopp, Madison B. Adolph, Lily I. Wu, Linda Chelico, Michael Emerman, Susan R Ross.
Humans express seven human APOBEC3 proteins, which can inhibit viruses and endogenous retroelements through cytidine deaminase activity. The seven paralogs differ in the potency of their antiviral effects, as well as in their antiviral targets. One APOBEC3, APOBEC3C, is exceptional as it has been found to only weakly block viruses and endogenous retroelements compared to other APOBEC3s. However, our positive selection analyses suggest that APOBEC3C has played a role in pathogen defense during primate evolution. Here, we describe a single nucleotide polymorphism in human APOBEC3C, a change from serine to isoleucine at position 188 (I188) that confers potent antiviral activity against HIV-1. The gain-of-function APOBEC3C SNP results in increased enzymatic activity and hypermutation of target sequences when tested in vitro, and correlates with increased dimerization of the protein. The I188 is widely distributed in human African populations, and is the ancestral primate allele, but is not found in chimpanzees or gorillas. Thus, while other hominids have lost activity of this antiviral gene, it has been maintained, or re-acquired, as a more active antiviral gene in a subset of humans. Taken together, our results suggest that APOBEC3C is in fact involved in protecting hosts from lentiviruses.
The APOBEC3 locus encodes seven cytidine deaminase proteins that inhibit endogenous retroelements, lentiviruses such as HIV-1, and other viruses . The APOBEC3 locus arose through duplication events on chromosome 22 of cytidine deaminase domains, resulting in single domain APOBEC3s (APOBEC3A, APOBEC3C, and APOBEC3H) and double-domain APOBEC3 genes (APOBEC3B, APOBEC3D, APOBEC3F, and APOBEC3G). In order for APOBEC3 proteins to restrict lentiviruses such as HIV-1, they are packaged into virions, brought to a target cell, and deaminate cytidines on ssDNA during reverse transcription, resulting in cytidine to uracil mutations in the viral genome. APOBEC3 proteins exert selective pressure on primate lentiviruses, which have evolved to encode a protein, Vif, which targets APOBEC3 proteins for proteasomal degradation.
APOBEC3C stood out among the seven human APOBEC3 paralogs as it little antiviral or anti-retroelement activity. We observed that the six APOBEC3s with known functions possess a conserved isoleucine at the residue homologous to APOBEC3C position 188, whereas APOBEC3C encodes a serine at this position. However, human APOBEC3C is, in fact, polymorphic at this site, and some humans encode an isoleucine, the residue that correlates with APOBEC3 antiviral/anti-retroelement function. This led us to hypothesize that APOBEC3C may have an as yet overlooked role as a restriction factor, and that the I188 variant may have enhanced antiviral activity compared to the more common variant, S188. APOBEC3C has evolved under positive selection in primates and within the interface of binding by the viral protein Vif, suggesting that this gene may have played a role in restriction of lentiviruses over primate evolution. Furthermore, we found that APOBEC3C I188 encodes a protein with increased antiviral activity, increased enzymatic activity, and the ability to dimerize in solution. Consistent with this conclusion, an artificial forced dimer of APOBEC3C S188 has vastly increased antiviral activity. We find that the isoleucine at position 188 was lost during hominid evolution but was either reacquired by some humans since humans split with our most recent common ancestor with chimpanzees, or alternatively, has never been lost as an allele and has been maintained as a polymorphism through several million years of hominoid evolution.