5'End Genomic Deletions and Enterovirus Persistence

  • Chapman, Nora M (PI)

Project: Research project

Project Details


DESCRIPTION (provided by applicant): The mutable RNA viruses are marvelously successful at adapting to exploit new environments. We will explore just such a newly discovered adaptation in this project, determining how the loss of a genomic region that is vital to replicational efficiency, allows an enterovirus to adapt to a different intracellular environment. Enteroviruses have been viewed as characteristically rapidly lytic, causing short-term infections. However, the discovery that group B coxsackieviruses (CVB) can delete sequence from the genomic 5'terminus (TD), yet maintain function and most importantly, persist for long periods of time post-infection in the heart or cell culture, has provided the grist with which to challenge that traditional view. Given that the 5'terminus of enterovirus RNA is involved in numerous functions for viral replication, deletion of as many as 49 nucleotides from the 5'end of the genome should be a dire event for the virus and indeed, it is. Among other things, viral replication slows dramatically and crippled positive strand RNA synthesis results in near 1 to 1 levels of positive to negative viral RNA in infected cells. The objective of this proposal is to characterize the role of hnRNPC1 in the mechanism by which CVB-TD populations become established. We hypothesize that under circumstances defined by the host cell - a lack of cytoplasmic hnRNPC1 in quiescent cells - an alternative form of positive strand viral RNA synthesis initiation occurs that leads to 5'end deletions of the positive strand genome. A single specific aim is proposed to accomplish this objective: we will determine whether a range of a terminal deletions occurs in quiescent cells due to altered viral transcriptional initiation, whether that range is limited by a requirement for part of structural domain I of the 5'nontranslated region and we will examine the structure and proteins of the CVB-TD replication complex. We will determine how selective lowering of cytoplasmic hnRNPC1 affects wildtype and TD CVB replication, if hnRNPC1 fails to bind the mutated 3'terminus of CVB- TD negative strand RNA and to what extent the wildtype process of uridylylation of the enterovirus protein primer is involved in CVB3-TD initiation of positive strand RNA synthesis. Cumulatively, this work will significantly expand our knowledge of this fascinating enterovirus lifestyle, providing insight into a novel mechanism by which enteroviruses can persist and cause chronic disease in humans. PUBLIC HEALTH RELEVANCE: This study is to determine the conditions and processes for generation of persistent enterovirus infections. These infections in hearts are associated with long term effects upon heart function including debilitating conditions such as dilated cardiomyopathy and chronic myocarditis. Understanding how selection of these variant viruses occurs and how these viruses replicate will provide the basis for developing treatments and detection of these viruses in heart, neurological and pancreatic disease.
Effective start/end date1/15/1012/31/13


  • National Institutes of Health: $292,150.00
  • National Institutes of Health: $294,030.00
  • National Institutes of Health: $294,030.00


  • Medicine(all)
  • Immunology and Microbiology(all)


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