Role of Epitranscriptomic and Epigenetic Modifications during the Lytic and Latent Phases of Herpesvirus Infections

Abstract

Herpesviruses are double-stranded DNA viruses occurring at a high prevalence in the human population and are responsible for a wide array of clinical manifestations and diseases, from mild to severe. These viruses are classified in three subfamilies (Alpha-, Beta- and Gammaherpesvirinae), with eight members currently known to infect humans. Importantly, all herpesviruses can establish lifelong latent infections with symptomatic or asymptomatic lytic reactivations. Accumulating evidence suggest that chemical modifications of viral RNA and DNA during the lytic and latent phases of the infections caused by these viruses, are likely to play relevant roles in key aspects of the life cycle of these viruses by modulating and regulating their replication, establishment of latency and evasion of the host antiviral response. Here, we review and discuss current evidence regarding epitranscriptomic and epigenetic modifications of herpesviruses and how these can influence their life cycles. While epitranscriptomic modifications such as m6A are the most studied to date and relate to positive effects over the replication of herpesviruses, epigenetic modifications of the viral genome are generally associated with defense mechanisms of the host cells to suppress viral gene transcription. However, herpesviruses can modulate these modifications to their own benefit to persist in the host, undergo latency and sporadically reactivate.

O‐glycosylation in viruses: A sweet tango

“…These include inducing ER stress, inhibiting Akt/mTOR signaling, and impeding autophagosome–lysosome fusion 15 , 16 . Besides, it was found that the inhibition of the HBP pathway increased HBV replication 17 . Mechanistically, it was pinpointed that sterile alpha motif and histidine/aspartic acid domain‐containing protein 1 (SAMHD1) is O‐GlcNAcylated at Ser93 17 .…”

“…Besides, it was found that the inhibition of the HBP pathway increased HBV replication 17 . Mechanistically, it was pinpointed that sterile alpha motif and histidine/aspartic acid domain‐containing protein 1 (SAMHD1) is O‐GlcNAcylated at Ser93 17 . As a deoxynucleotide triphosphate triphosphohydrolase (dNTPase), SAMHD1 functions by converting deoxynucleoside triphosphates (dNTPs) into their corresponding deoxynucleosides and inorganic triphosphates 18 .…”

“…However, the incorrect processing of host nucleic acids results in the sustained activation of the innate immune system, which ultimately contributes to the persistent activation of the immune system. O‐GlcNAcylation has been found to stabilize SAMHD1, promote its tetramer formation, and upregulate its dNTPase activity 17 , again restricting viral DNA synthesis. Taken together, at the early stage of HBV infection (before progression into HCC), O‐GlcNAcylation might attenuate HBV replication by downregulating the autophagy pathway 16 or upregulating the interferon (IFN)‐induced SAMHD1 in the host cells (Figure 1 ) 17 .…”

Mechanisms of T cell evasion by Epstein-Barr virus and implications for tumor survival

“…Gp350, a gp commonly targeted by neutralizing antibodies, is also important for entry into both B and epithelial cells ( 29 ). Once infection is established, the virus can enter lytic or latent phases of infection ( 30 ). Latent infection in B cells inhibits apoptosis and results in B cell transformation through the expression of a set of viral latency genes that allow for persistence over time in a quiescent state ( 31 , 32 ).…”

Contribution of carbohydrate-related metabolism in Herpesvirus infections

“…Once the genomes of herpesviruses enter the nucleus of infected cells, these viruses will hijack and modulate cellular processes to carry out their replication cycles, altogether altering transcription, splicing, translation, and post-translational modifications, among other processes ( Iarovaia et al., 2021 ; Imbert and Langford, 2021 ; Liao and Garcia-Blanco, 2021 ; Lucic et al., 2021 ; Soto et al., 2022 ). Moreover, herpesvirus infections are also known to control epitranscriptomic and epigenetic processes ( Soto et al., 2022 ), endosome trafficking ( Tognarelli et al., 2021 b), and remodel the cytoskeleton ( Naghavi and Walsh, 2017 ; Robinson et al., 2018 ; Stradal and Schelhaas, 2018 ; Walsh and Naghavi, 2019 ). Additionally, viral infections also modulate cellular signaling pathways, such as those related to phosphatidylinositol phosphate kinases (PIKs), mitogen-activated protein kinases (MAPK), toll-like receptors (TLRs), and interferon (IFN)-related pathways, to name a few ( Beziau et al., 2020 ; Brezgin et al., 2021 ; Chander et al., 2021 ).…”