Genetic Editing of Herpes Simplex Virus 1 and Epstein-Barr Herpesvirus Genomes by Human APOBEC3 Cytidine Deaminases in Culture and In Vivo

Abstract

The seven-gene human APOBEC3 (A3) cytidine deaminase locus came to the fore with the identification of APOBEC3G (A3G) as the interaction partner of the human immunodeficiency virus (HIV) Vif protein (8,16,26,29,30,43,57). These enzymes belong to a larger group that can edit nucleic acids, of which activation-induced cytidine deaminase (AICDA), responsible for class switch recombination and somatic hypermutation of rearranged immunoglobulin V region genes, is perhaps the most widely known (11). All functional A3 enzymes show specificity for single-stranded DNA (ssDNA). Since the reaction product is uridine (dU), A3 activity results in DNA peppered by C 3 U substitutions, referred to as hypermutants. Editing can range from a few cytidine targets to over 80% (2,3,8,16,26,29,30,49,54). To a good first approximation, all A3 enzymes preferentially edit ssDNA when the edited base is 5Ј flanked by thymidine or cytidine, i.e., TpC and CpC. In contrast, AICDA prefers GpC and ApC (2,

SAMHD1 Restricts Herpes Simplex Virus 1 in Macrophages by Limiting DNA Replication

“…The same strategies used by restriction factors to block retroviruses may also be employed to limit infection of DNA viruses. For example, both the APOBEC3 and tetherin/BST2 proteins have been suggested to inhibit herpesvirus infection (19,20). The human SAMHD1 protein was recently identified as a retroviruses restriction factor (8,9).…”

The MOV10 Helicase Inhibits LINE-1 Mobility

“…To control massively activated LINE-1, germ line cells express a special type of small RNA named piRNA (piwi-interacting RNA) that arms Piwi (P-element induced wimpy testis) proteins to suppress LINE-1 (25,26). Furthermore, it has been reported that APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins, which inhibit the infection of a broad range of viruses particularly retroviruses (27)(28)(29)(30)(31), also provide another mechanism to control LINE-1 (32)(33)(34). It appears that cells manage to use the same mechanism to protect themselves from either extracellular or intracellular insults that share common biochemical features.…”

Epstein-Barr Virus-Encoded miRNAs in Epstein-Barr Virus-Related Malignancy

“…A3A, A3G, and activation-induced cytidine deaminase (AICDA) can edit what is thought to be a small fraction of HSV genome in an experimental setting without seriously impacting viral titers. Hyper-editing was found to occur in HSV genomes recovered from four of eight uncultured buccal lesions, but the phenomenon was not restricted to HSV; hyper-mutated EBV genomes were readily recovered from four of five established cell lines, indicating that episomes are also vulnerable to editing 67 . These findings suggest that the widely expressed A3C cytidine deaminase can function as a restriction factor for some human herpesviruses.…”

“…66 Mechanistic analysis of this sequence variability has recently been reported by Suspène et al 67 Human APOBEC3 cytidine deaminases target and edit singlestranded DNA, which can be of viral, mitochondrial, or nuclear origin. Retroviral genomes, such those of HIV, deficient in the vif gene, and hepatitis B virus, are particularly vulnerable.…”