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Front. Immunol. | doi: 10.3389/fimmu.2018.03032

APOBEC3G Regulation of the Evolutionary Race between Adaptive Immunity and Viral Immune Escape is Deeply Imprinted in the HIV Genome

  • 1Memorial University of Newfoundland, Canada

APOBEC3G (A3G) is a host enzyme that mutates the genomes of retroviruses like HIV. Since A3G is expressed pre-infection, it has classically been considered an agent of innate immunity. We and others previously showed that the impact of A3G-induced mutations on the HIV genome extends to adaptive immunity also, by generating cytotoxic T cell (CTL) escape mutations. Accordingly, HIV genomic sequences encoding CTL epitopes often contain A3G-mutable “hotspot” sequence motifs, presumably to channel A3G action towards CTL escape. Here, we studied the depths and consequences of this apparent viral genome co-evolution with A3G. We identified all potential CTL epitopes in Pol, Gag, Nef and Env restricted to several HLA class I alleles. We simulated A3G-induced mutations within CTL epitope-encoding sequences, and flanking regions. From the immune recognition perspective, we analyzed how A3G-driven mutations are predicted to impact CTL-epitope generation through modulating proteasomal processing and HLA class I binding. We found that A3G mutations were most often predicted to result in diminishing/abolishing HLA-binding affinity of peptide epitopes. From the viral genome evolution perspective, we evaluated enrichment of A3G hotspots at sequences encoding CTL epitopes and included control sequences in which the HIV genome was randomly shuffled. We found that sequences encoding immunogenic epitopes exhibited a selective enrichment of A3G hotspots, which were strongly biased to translate to non-synonymous amino acid substitutions. When superimposed on the known mutational gradient across the entire length of the HIV genome, we observed a parallel gradient of A3G hotspot enrichment, and an HLA-specific gradient pattern of the potential of A3G hotspots to lead to CTL escape mutations. These data illuminate the depths and extent of the co-evolution of the viral genome to subvert the host mutator A3G.

Keywords: CTL epitope, APOBEC3G (A3G), HIV, immune escape, Viral Evolution

Received: 15 Jul 2018; Accepted: 07 Dec 2018.

Edited by:

Gkikas Magiorkinis, National and Kapodistrian University of Athens, Greece

Reviewed by:

Jean-Christophe Paillart, Université de Strasbourg, France
Matteo Negroni, Center for the National Scientific Research (CNRS), France
Tara P. Hurst, Abcam (United Kingdom), United Kingdom  

Copyright: © 2018 Larijani, Borzooee, Joris and Grant. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Mani Larijani, Memorial University of Newfoundland, St. John's, Canada,