Footprint of the host restriction factors APOBEC3 on the genome of human viruses

Abstract

APOBEC3 enzymes are innate immune effectors that introduce mutations into viral genomes. These enzymes are cytidine deaminases which transform cytosine into uracil. They preferentially mutate cytidine preceded by thymidine making the 5'TC motif their favored target. Viruses have evolved different strategies to evade APOBEC3 restriction. Certain viruses actively encode viral proteins antagonizing the APOBEC3s, others passively face the APOBEC3 selection pressure thanks to a depleted genome for APOBEC3-targeted motifs. Hence, the APOBEC3s left on the genome of certain viruses an evolutionary footprint. The aim of our study is the identification of these viruses having a genome shaped by the APOBEC3s. We analyzed the genome of 33,400 human viruses for the depletion of APO-BEC3-favored motifs. We demonstrate that the APOBEC3 selection pressure impacts at least 22% of all currently annotated human viral species. The papillomaviridae and polyomaviridae are the most intensively footprinted families; evidencing a selection pressure acting genome-wide and on both strands. Members of the parvoviridae family are differentially targeted in term of both magnitude and localization of the footprint. Interestingly, a massive APOBEC3 footprint is present on both strands of the B19 erythroparvovirus; making this viral genome one of the most cleaned sequences for APOBEC3-favored motifs. We also identified the endemic coronaviridae as significantly footprinted. Interestingly, no such footprint has been detected on the zoonotic MERS-CoV, SARS-CoV-1 and SARS-CoV-2 coronaviruses. In addition to viruses that are footprinted genome-wide, certain viruses are footprinted only on very short sections of their genome. That is the case for the gamma-herpesviridae and adenoviridae where the footprint is localized on the lytic origins of replication. A mild footprint can also be detected on the negative strand of the reverse transcribing HIV-1, HIV-2, HTLV-1 and HBV viruses. Together, our data illustrate the extent of the APOBEC3 selection pressure on the human viruses and identify new putatively APOBEC3-targeted viruses.

APOBECs and Herpesviruses

“…Whether or not beta-herpesviruses also possess an A3 counteraction mechanism is currently unknown, but precedence dictates that any entity with susceptible ssDNA (e.g., DNA replication or transcription intermediates) should be theoretically susceptible to A3 enzymes, including retroviruses, small and large DNA viruses, and sometimes, unfortunately, also cellular chromosomal DNA. Indeed, in a recent pan-viral survey of APOBEC mutation signatures, several types of mammalian DNA viruses including ssDNA and dsDNA viruses showed varying degrees of APOBEC mutation signature [ 55 ].…”

“…This general strategy has been applied to herpesviruses specifically [ 21 , 53 , 54 ], as well as to all publicly available viral sequences [ 55 ]. The first analysis of the APOBEC mutation signature in herpesviruses reported a strong under-representation of 5’-TC motifs in VZV, EBV, KSHV and to lesser extents in HSV-1, HCMV, and the other human herpesviruses [ 54 ].…”

“…The same study also indicated that the EBV origin of replication oriP may be a hotspot for A3-catalyzed 5’-TC-to-TT mutation. In addition, AID may contribute to EBV mutagenesis by deaminating preferred 5’-WRC motifs in the viral genomes within B lymphocytes [ 53 , 55 ].…”

The von Hippel–Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases

“…Evidence indicates that the 7 members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) family of cellular cytidine deaminases (A3A, -B, -C, D, F, G, and -H) have been positively selected throughout primate evolution by their interplay with endogenous retroelements and exogenous pathogens. [1][2][3][4][5] This conserved deaminase catalytic function results in different A3s introducing mutations in both exogenous and endogenous single-stranded DNA (ssDNA) substrates. 6 Variation in levels of A3s in different human cell types is associated with differences in pathogenesis of human immunodeficiency virus (HIV) infection and cancer, albeit in opposite directions.…”

“…10,11,13,[19][20][21] Furthermore, A3-mediated mutations have also been implicated in the editing of a broad range of other viral genomes. 5 In some such cases, A3 proteins have been shown to also restrict replication of these other viruses. 22 On the other hand, nuclear-localized A3A, A3B, and A3H haplotype I (A3H I) are a source of chromosomal mutations in cancer cells that has been associated with accelerated progression in a range of cancers.…”