Mutational pressure by host APOBEC3s more strongly affects genes expressed early in the lytic phase of herpes simplex virus-1 (HSV-1) and human polyomavirus (HPyV) infection

Abstract

Herpes-Simplex Virus 1 (HSV-1) infects most humans when they are young, sometimes with fatal consequences. Gene expression occurs in a temporal order upon lytic HSV-1 infection: immediate early (IE) genes are expressed, then early (E) genes, followed by late (L) genes. During this infection cycle, the HSV-1 genome has the potential for exposure to APOBEC3 (A3) proteins, a family of cytidine deaminases that cause C>U mutations on single-stranded DNA (ssDNA), often resulting in a C>T transition. We developed a computational model for the mutational pressure of A3 on the lytic cycle of HSV-1 to determine which viral kinetic gene class is most vulnerable to A3 mutations. Using in silico stochastic methods, we simulated the infectious cycle under varying intensities of A3 mutational pressure. We found that the IE and E genes are more vulnerable to A3 than L genes. We validated this model by analyzing the A3 evolutionary footprints in 25 HSV-1 isolates. We find that IE and E genes have evolved to underrepresent A3 hotspot motifs more so than L genes, consistent with greater selection pressure on IE and E genes. We extend this model to two-step infections, such as those of polyomavirus, and find that the same pattern holds for over 25 human Polyomavirus (HPyVs) genomes. Genes expressed earlier during infection are more vulnerable to mutations than those expressed later.

Variability in Codon Usage in Coronaviruses Is Mainly Driven by Mutational Bias and Selective Constraints on CpG Dinucleotide

“…Furthermore, as detailed in the methods and to prevent biases introduced by annotation errors in the SARS-COV-2 genomes, we limited ourselves to the best-annotated open reading frames, namely ORF1ab, S, E, M and N. These global analyses may have erased any potential signal for differential composition and/or CUB between open reading frames. It is conceivable that different open reading frames in the CoV genomes may present differences in their nucleotide composition and CUB, as is the case in many other viruses [ 30 , 91 ]. This is actually more relevant in the case of CoVs, because of the (+)ssRNA nature of the viral genome.…”

Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases

“…HIV-1 and related retroviruses are thought to be primary targets of A3 enzymes due to obligate ssDNA replication intermediates, abundant evidence for A3-catalyzed hypermutation of viral genomes, and a potent A3 counteraction mechanism. Reports of DNA viruses exhibiting signatures of A3-mediated mutagenesis suggest that these viruses may also be susceptible to restriction by A3 enzymes ( Harris and Dudley, 2015 ; Shapiro et al, 2021 ), although the identification of viral antagonists has been challenging. We recently discovered that the large double-stranded (ds)DNA herpesvirus EBV uses a two-pronged approach to counteract the antiviral activity of A3B.…”

Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases

“…These studies have been essential to our understanding of how viruses adapt to overcome innate host defenses and, collectively, highlight the importance of elucidating structure-function relationships between proteins at the hostpathogen interface.HIV-1 and related retroviruses are thought to be the main viral targets of A3 enzymes due to obligate ssDNA replication intermediates, abundant evidence for A3-catalyzed hypermutation of viral genomes, and a potent A3 counteraction mechanism. Reports of DNA viruses exhibiting signatures of A3-mediated mutagenesis suggest that these viruses may also be susceptible to restriction by A3 enzymes [2,24], although the identification of viral antagonists has been challenging. We recently discovered that the large double-stranded (ds)DNA herpesvirus Epstein-Barr Virus (EBV) uses a two-pronged approach to counteract the antiviral activity of A3B.…”