Epigenetics and Genetics of Viral Latency

Abstract

Viral latency can be considered a metastable, nonproductive infection state that is capable of subsequent reactivation to repeat the infection cycle. Viral latent infections have numerous associated pathologies, including cancer, birth defects, neuropathy, cardiovascular disease, chronic inflammation, and immunological dysfunctions. The mechanisms controlling the establishment, maintenance, and reactivation from latency are complex and diversified among virus families, species, and strains. Yet, as examined in this review, common properties of latent viral infections can be defined. Eradicating latent virus has become an important but elusive challenge and will require a more complete understanding of the mechanisms controlling these processes.

Keywords: DNA virus; epigenetics; genetics; herpesvirus; latency; reactivation; virus.

Figure 1. Overview of the Dynamic Host-Pathogen Conflict Driving Viral Latency

(A) Viruses exploit and reprogram host antiviral resistances to adopt a stable latent infection. (B) Host intrinsic resistances that restrict productive lytic cycle infection can drive the formation of latency. DNA-damage sensing and chromatin assembly factors that limit productive infection can promote latent episomes and stable chromatin formation. Latency-associated noncoding RNA evade immune detection and reroute inflammatory pathways to promote conditions permissive for latent infection (see text for details).

Figure 2. Comparing Latency Origins and Episome Maintenance Elements from Different Viruses

(A) Episomal genomes for EBV, KSHV, HPV, HBV, CMV, and HSV have been identified during latent infection. Genome integration at telomeres are found forMDV, HHV6, and GaV2 latency, while retroviruses, HTLV, and HIV integrate more randomly. (B) Episome maintenance factors for HPV E2, EBV EBNA1, and KSHV LANA and their related mechanisms of metaphase chromosome tethering.

Figure 3. Reactivation Pathways

Reactivation from latency can be initiated from various extrinsic and intrinsic signals, including host cell terminal differentiation, DNA damage and repair signaling (DDR), and various epigenetic deregulators that perturb viral chromatin. Metabolic stress and apoptosis can alter the activity of chromatin regulatory factors, like SIRT1 and PARP1. Both DNA and histones can be subject to demethylation to reactivate viral lytic cycle gene expression. Host factors, including HCF1 and Granzyme M, can induce expression of viral tegument proteins to animate the early stages of reactivation. Inflammatory cytokines can alter the balance innate immune signaling to promote lytic cycle gene activation. Partial lytic gene expression may occur frequently among populations of latently infected cells (see text for details).