Conserved Footprints of APOBEC3G on Hypermutated Human Immunodeficiency Virus Type 1 and Human Endogenous Retrovirus HERV-K(HML2) Sequences

Abstract

The human polynucleotide cytidine deaminases APOBEC3G (hA3G) and APOBEC3F (hA3F) are antiviral restriction factors capable of inducing extensive plus-strand guanine-to-adenine (G-to-A) hypermutation in a variety of retroviruses and retroelements, including human immunodeficiency virus type 1 (HIV-1). They differ in target specificity, favoring plus-strand 5GG and 5GA dinucleotide motifs, respectively. To characterize their mutational preferences in detail, we analyzed single-copy, near-full-length HIV-1 proviruses which had been hypermutated in vitro by hA3G or hA3F. hA3-induced G-to-A mutation rates were significantly influenced by the wider sequence context of the target G. Moreover, hA3G, and to a lesser extent hA3F, displayed clear tetranucleotide preference hierarchies, irrespective of the genomic region examined and overall hypermutation rate. We similarly analyzed patient-derived hypermutated HIV-1 genomes using a new method for estimating reference sequences. The majority of these, regardless of subtype, carried signatures of hypermutation that strongly correlated with those induced in vitro by hA3G. Analysis of genome-wide hA3-induced mutational profiles confirmed that hypermutation levels were reduced downstream of the polypurine tracts. Additionally, while hA3G mutations were found throughout the genome, hA3F often intensely mutated shorter regions, the locations of which varied between proviruses. We extended our analysis to human endogenous retroviruses (HERVs) from the HERV-K(HML2) family, finding two elements that carried clear footprints of hA3G activity. This constitutes the most direct evidence to date for hA3G activity in the context of natural HERV infections, demonstrating the involvement of this restriction factor in defense against retroviral attacks over millions of years of human evolution.

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…Investigation of the sequences surrounding the edited nucleotides revealed dominance of adenosines at position + 2 relative to the editing site (GxA→AxA motif; the underlined G is the editing site; Methods and Supplementary Table S1). This is in agreement with previous experimental studies [14][15][16][17][18][19][20]23,24 and supports the identification of these mismatches as an outcome of mouse APOBEC3 activity.…”

“…This process is thus called DNA editing. In recent years, it was shown that active LTR (long terminal repeat) retrotransposons, which are endogenous retroviruses, can also be edited [14][15][16][17][18][19][20][21] . However, the impact of DNA editing on genome variability has not been explored to date 22 .…”

Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

“…Although that study confirmed the previously described bias toward G-to-A mutations in HIV-1 (30-32), APOBEC3G or APOBEC3F footprints could not be reliably detected. We previously determined the tri-and tetranucleotide target preferences for APOBEC3F and APOBEC3G (12), which enabled us to study the influence of the downstream nucleotide on Non-synonymous mutation…”

“…During reverse transcription, APOBEC3F and APOBEC3G induce cytidine-to-uridine (C-to-U) deamination of single-stranded minus-strand HIV-1 DNA, which generates guanosine-to-adenosine (G-to-A) mutations in plus-strand DNA (3,(5)(6)(7)(8)(9)(10)(11). These G-to-A mutations occur in APOBEC3F-and APOBEC3G-favored di-, tri-and tetranucleotide contexts (the GGnn-to-AGnn and GAnn-to-AAnn contexts, respectively [12]) (the mutated nucleotide residue is underlined). The remaining APOBEC3 proteins favor the same dinucleotide context as APOBEC3F.…”

Association between Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide-Like 3B (APOBEC3B) Deletion with HIV-1 Acquisition and AIDS among North Indian Population

“…APOBEC3 genes are located on chromosome 22 [11] and these proteins acts upon viral nucleic acids as a form of intrinsic host defense [12]. A3 (APOBEC3) enzymes are capable of editing single-stranded DNA and recognize specific target sequences [13][14][15][16]. It plays an important role in the innate immune system and acts upon host defense against exogenous viruses and endogenous retro elements [17][18][19][20].…”