Role of the host restriction factor APOBEC3 on papillomavirus evolution

Abstract

More than 270 different types of papillomaviruses have been discovered in a wide array of animal species. Despite the great diversity of papillomaviruses, little is known about the evolutionary processes that drive host tropism and the emergence of oncogenic genotypes. Although host defense mechanisms have evolved to interfere with various aspects of a virus life cycle, viruses have also coevolved copious strategies to avoid host antiviral restriction. Our and other studies have shown that the cytidine deaminase APOBEC3 family members edit HPV genomes and restrict virus infectivity. Thus, we hypothesized that host restriction by APOBEC3 served as selective pressure during papillomavirus evolution. To test this hypothesis, we analyzed the relative abundance of all dinucleotide sequences in full-length genomes of 274 papillomavirus types documented in the Papillomavirus Episteme database (PaVE). Here, we report that TC dinucleotides, the preferred target sequence of several human APOBEC3 proteins (hA3A, hA3B, hA3F, and hA3H), are highly depleted in papillomavirus genomes. Given that HPV infection is highly tissue-specific, the expression levels of APOBEC3 family members were analyzed. The basal expression levels of all APOBEC3 isoforms, excluding hA3B, are significantly higher in mucosal skin compared with cutaneous skin. Interestingly, we reveal that Alphapapillomaviruses (alpha-PVs), a majority of which infects anogenital mucosa, display the most dramatic reduction in TC dinucleotide content. Computer modeling and reconstruction of ancestral alpha-PV genomes suggest that TC depletion occurred after the alpha-PVs diverged from their most recent common ancestor. In addition, we found that TC depletion in alpha-PVs is greatly affected by protein coding potential. Taken together, our results suggest that PVs replicating in tissues with high APOBEC3 levels may have evolved to evade restriction by selecting for variants that contain reduced APOBEC3 target sites in their genomes.

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

“…It is unclear whether the virus directly induces the A3B response to such a level as to avoid restriction while generating additional genetic diversity for better fitness as has been observed in HIV-1 (40,41). Our data are also consistent with recent reports that point to possible roles of A3 enzymes during HPV evolution (42). Interestingly, we also identified a strong asymmetry in the abundance TC or its reverse complement GA that corresponds to the direction of both transcription and viral genomic DNA lagging-strand replication.…”

Evasion of host immune defenses by human papillomavirus

“…However, since TLR9 expression is significantly downregulated in cells expressing the HPV oncoprotein E7 as described above, it is likely that HPV infection and viral gene expression may be influenced by TLR9 responses. Similar to many other small DNA viruses, such as adenovirus and parvovirus, papillomavirus genomes have significantly lower contents of CpG dinucleotides than expected by random chance (Upadhyay et al, 2013; Upadhyay and Vivekanandan, 2015; Warren et al, 2015a). In a recent publication, we calculated the ratio of observed vs. expected (O/E) counts of all dinucleotides in the genomes of all 274 PVs deposited in the Papillomavirus Episteme (PaVE) database (Warren et al, 2015a).…”

“…Similar to many other small DNA viruses, such as adenovirus and parvovirus, papillomavirus genomes have significantly lower contents of CpG dinucleotides than expected by random chance (Upadhyay et al, 2013; Upadhyay and Vivekanandan, 2015; Warren et al, 2015a). In a recent publication, we calculated the ratio of observed vs. expected (O/E) counts of all dinucleotides in the genomes of all 274 PVs deposited in the Papillomavirus Episteme (PaVE) database (Warren et al, 2015a). We revealed that CpG dinucleotides are the most underrepresented dinucleotide in the genomes of all PV types, except two bird PVs.…”

“…Interestingly, TpC dinucleotides, the preferred dinucleotide target site of many A3s, are dramatically underrepresented in papillomavirus genomes. TpC depletion was most dramatic amongst the Alphapapillomaviruses which preferably infect mucosal skin such as the cervicovaginal and oral regions (Warren et al, 2015a). Surprisingly, mucosal skin expresses significantly higher basal levels of all A3 isoforms (except A3B) when compared to cutaneous skin.…”

Novel recombinant papillomavirus genomes expressing selectable genes

“…Long-term expression of (virally transduced) transgenes is an active field of study1213, but it has been shown that CpG motifs located within the promoter and/or open reading frame (ORF) are associated with a loss of transgene expression1415. Furthermore, the HPV18 genome has a decreased CpG content16, suggesting that CpG motifs may affect the fitness of these viruses17.…”