Persistent Enterovirus Infection: Little Deletions, Long Infections

Abstract

Enteroviruses have now been shown to persist in cell cultures and in vivo by a novel mechanism involving the deletion of varying amounts of the 5′ terminal genomic region termed domain I (also known as the cloverleaf). Molecular clones of coxsackievirus B3 (CVB3) genomes with 5′ terminal deletions (TD) of varying length allow the study of these mutant populations, which are able to replicate in the complete absence of wildtype virus genomes. The study of TD enteroviruses has revealed numerous significant differences from canonical enteroviral biology. The deletions appear and become the dominant population when an enterovirus replicates in quiescent cell populations, but can also occur if one of the cis-acting replication elements of the genome (CRE-2C) is artificially mutated in the element’s stem and loop structures. This review discusses how the TD genomes arise, how they interact with the host, and their effects on host biology.

Major Group-B Enterovirus populations deleted in the noncoding 5’ region of genomic RNA modulate activation of the type I interferon pathway in cardiomyocytes and induce myocarditis

“…The emergence of major 5’-terminally deleted RNA forms of group B coxsackievirus (CVB-5’TD) has been associated with myocarditis in both mice and humans [ 2 – 4 , 10 , 13 , 16 , 20 , 32 ]. While type I interferon (IFN) signaling is known to be critical for an efficient innate immune response against EV-B in mouse and human myocarditis, the relationship between CVB-5’TD RNA forms and type I IFN signaling in cardiomyocytes remains to be explored.…”

“…These EVB-5’TD populations were characterized by a decrease in ratios of positive to negative [(+)/(−)] RNA strands, and low viral protein synthesis activities [ 6 , 8 , 10 , 11 ]. Taken together these clinical and experimental findings suggest that these replicative EVB-5’TD populations are associated with the development of acute or chronic myocarditis in humans and mouse models [ 10 , 12 , 13 ].…”

Global landscape of coxsackieviruses in human health

“…Particularly, CVs present a high diversity within the Enterovirus genus and are categorized into three EV species: A (CVA2–8, CVA10, CVA12, CV14 and CVA16), B (CVA9, and CVB1–6) and C (CVA1, CVA11, CVA13, CVA17, CVA19–22, CVA24) being responsible for a wide variety of clinical diseases ( Table 1 ). Even though CVs are typically thought of as a lytic virus, emerging evidence suggests that persistent CV infection can occur in some pathologies and individuals immunodeficient ( Sin et al, 2015 ; Chapman, 2022 ; Mastrodomenico et al . ; Nekoua et al, 2022 ).…”

Enterovirus-Cardiomyocyte Interactions: Impact of Terminally Deleted Genomic RNAs on Viral and Host Functions

“…The exact mechanisms driving the evolution from acute to persistent cardiac infection are not fully understood. Previous studies revealed that during both acute fulminant myocarditis and dilated cardiomyopathy (DCM), the viral RNA genome undergoes 5' terminal deletions (10,(13)(14)(15). Deletions in patient samples and murine models ranged from 8 to 50 nucleotides (10,14), while genetically-engineered CVB3 genomic RNAs harboring deletions of up to 78 nucleotides were able to replicate in cell culture, albeit very inefficiently (16).…”