Structural and Virological Studies of the Stages of Virus Replication That Are Affected by Antirhinovirus Compounds

Zhang, Ying; Simpson, A.A.; Ledford, Rebecca M.; Bator, Carol M.; Chakravarty, S.; Skochko, G.A.; Demenczuk, Tina M.; Watanyar, Adiba; Pevear, Daniel C.; Rossmann, Michael G.

doi:10.1128/jvi.78.20.11061-11069.2004

Cited by 60 publications

(56 citation statements)

References 44 publications

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“…In contrast, adult c-kit + cells failed to express detectable levels of viral protein or significant amounts of infectious virus. These differences are consistent with clinical studies suggesting that infants are much more susceptible to CVB3 infections than adults [27], [28], [29]. As the course of infection progressed, a majority of juvenile c-kit + cells exhibited cytopathic effects, detached from the surface of the culture dish and fragmented into apoptotic bodies.…”

Section: Resultssupporting

confidence: 88%

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

et al. 2014

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Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

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Section: Resultssupporting

confidence: 88%

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

et al. 2014

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“…Secondary structure calculations of HRV-A34 VP1 using the CDSSTR algorithm and reference set 4 indicated the presence of 10% α-helix and 30% β-sheet content (Table 2), comparable to the published secondary structure of HRV-A1A VP1 ([29]; pdb: 1R1A). The percentages of secondary structure of recombinant HRV-B14 VP1 was also similar to published data on native HRV-B14 VP1 ([30]; pdb: 1NCQ).…”

Section: Resultssupporting

confidence: 86%

Species-Specific and Cross-Reactive IgG1 Antibody Binding to Viral Capsid Protein 1 (VP1) Antigens of Human Rhinovirus Species A, B and C

et al. 2013

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BackgroundHuman rhinoviruses (HRV) are associated with upper and lower respiratory illnesses, including severe infections causing hospitalization in both children and adults. Although the clinical significance of HRV infections is now well established, no detailed investigation of the immune response against HRV has been performed. The purpose of this study was to assess the IgG1 antibody response to the three known HRV species, HRV-A, -B and -C in healthy subjects.MethodsRecombinant polypeptides of viral capsid protein 1 (VP1) from two genotypes of HRV-A, -B and -C were expressed as glutathione S-transferase (GST) fusion proteins and purified by affinity and then size exclusion chromatography. The presence of secondary structures similar to the natural antigens was verified by circular dichroism analysis. Total and species-specific IgG1 measurements were quantitated by immunoassays and immunoabsorption using sera from 63 healthy adults.ResultsMost adult sera reacted with the HRV VP1 antigens, at high titres. As expected, strong cross-reactivity between HRV genotypes of the same species was found. A high degree of cross-reactivity between different HRV species was also evident, particularly between HRV-A and HRV-C. Immunoabsorption studies revealed HRV-C specific titres were markedly and significantly lower than the HRV-A and HRV-B specific titres (P<0.0001). A truncated construct of HRV-C VP1 showed greater specificity in detecting anti-HRV-C antibodies.ConclusionsHigh titres of IgG1 antibody were bound by the VP1 capsid proteins of HRV-A, -B and -C, but for the majority of people, a large proportion of the antibody to HRV-C was cross-reactive, especially to HRV-A. The improved specificity found for the truncated HRV-C VP1 indicates species-specific and cross-reactive regions could be defined.

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“…The pocket residues important for A16 and B14 drug binding, especially for pleconaril, are well described (Zhang et al, 2004; Ledford et al, 2005). An inclusive contact list within the VP1 β-core was generated with Endscript (Gouet and Courcelle, 2002), by evaluating the 28 RV-A+B structures co-crystalized with drugs and returning every residue within 4 Å of any drug, in any virus.…”

Section: Resultsmentioning

confidence: 99%

Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance

et al. 2014

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Human rhinoviruses of the RV-C species are recently discovered pathogens with greater clinical significance than isolates in the RV-A+B species. The RV-C cannot be propagated in typical culture systems; so much of the virology is necessarily derivative, relying on comparative genomics, relative to the better studied RV-A+B. We developed a bioinformatics-based structural model for a C15 isolate. The model showed the VP1–3 capsid proteins retain their fundamental cores relative to the RV-A+B, but conserved, internal RV-C residues affect the shape and charge of the VP1 hydrophobic pocket that confers antiviral drug susceptibility. When predictions of the model were tested in organ cultures or ALI systems with recombinant C15 virus, there was a resistance to capsid-binding drugs, including pleconaril, BTA-188, WIN56291, WIN52035 and WIN52084. Unique to all RV-C, the model predicts conserved amino acids within the pocket and capsid surface pore leading to the pocket may correlate with this activity.

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Structural and Virological Studies of the Stages of Virus Replication That Are Affected by Antirhinovirus Compounds

Cited by 60 publications

References 44 publications

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

Species-Specific and Cross-Reactive IgG1 Antibody Binding to Viral Capsid Protein 1 (VP1) Antigens of Human Rhinovirus Species A, B and C

Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance

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