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

Abstract

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 toward 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 Gag, Pol, Env, and Nef 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 gradient of A3G hotspot enrichment, and an HLA-specific 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.

USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication

“…Accumulating evidence indicates that A3G induces sub-lethal hypermutations in the Vif-positive HIV-1 genome and plays an important role in the production of defective proviral DNA in the HIV-1 reservoir (Borzooee et al, 2018; Cuevas et al, 2015; De Pasquale et al, 2013; Kieffer et al, 2005). A3G-induced hypermutations in vif and env genes of proviruses in vivo have been reported by several groups (Fourati et al, 2010; Simon et al, 2005).…”

“…The development of A3G-mediated sub-lethal hypermutations in the Vif-positive HIV-1 genome in vitro and in vivo has been widely accepted (Borzooee et al, 2018; Cuevas et al, 2015; De Pasquale et al, 2013; Jern et al, 2009; Kieffer et al, 2005; Kim et al, 2010; Mulder et al, 2008; Sadler et al, 2010; Zhang et al, 2003). Given that USP49 protects A3G from the Vif-dependent and Vif-independent degradation pathway, it is important to study the possible correlation between USP49 expression and A3G expression, and subsequently HIV-1 disease progression.…”

“…CBF-β can increase the stability of HIV-1 Vif and promote assembly of the Vif-Cullin 5-E3-ubiquitin-ligase complex (Jäger et al, 2011; Zhang et al, 2011). Further, some clinical in vivo analyses of Vif-positive HIV-1 quasispecies indicated that A3G mediates lethal hypermutations and leads to the accumulation of G-to-A hypermutations in the Vif-positive HIV-1 genome, subsequently resulting in a large number of defective proviruses in the viral reservoir (Borzooee et al, 2018; Cuevas et al, 2015; De Pasquale et al, 2013; Kieffer et al, 2005). The expression level of A3G is also correlated with viremia and CD4 counts in the peripheral blood (Amoêdo et al, 2011; Jin et al, 2005; Kourteva et al, 2012; Pace et al, 2006; Ulenga et al, 2008; Vázquez-Pérez et al, 2009).…”

Effects of APOBEC3G's Cytidine Deaminase Activity on Retroviral Evolution

“…It has been found that some A3 proteins may indirectly contribute to retroviral evolution, where the cytidine deaminase activity of the A3 protein helps the virus to acquire mutations that will make it more fit. Studies by Kim [3,5,10]. It was also shown that A3 proteins can mutate viruses so that they can use different receptors on the cell surface for entry into the host cell [5].…”

“…Immune escape refers to a situation where a pathogen evades detection by the host's immune system. In the case of retroviruses, this immune escape can be aided by A3 proteins [1,10,13]. As mentioned earlier, A3 proteins may sometimes cause sublethal mutations, which could help the virus to avoid detection by cytotoxic T cells (CTL), which kill infected cells [1,10,13].…”