Pathogenicity for humans of human rhinovirus type 2 mutants resistant to or dependent on chalcone Ro 09-0410

Yasin, S. R.; Al‐Nakib, W.; Tyrrell, D. A. J.

doi:10.1128/aac.34.6.963

Cited by 20 publications

(11 citation statements)

References 15 publications

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“…In that study, several poliovirus mutants displayed intermediate levels of resistance (2-to 4-fold increases in inhibitory concentrations), while one variant was highly resistant (over a 10-fold increase) to neutralization. The levels of sICAM-1 resistance of HRV-39 variants that we have reported are comparable to the resistance levels previously observed for single-step to sevenfold increases in EC50s) (10) (20). One study reported the recovery of HRV-9 resistant to a capsid-binding agent, R618367, after a human experimental infection (6), in which 32% of the treated volunteers shed resistant viruses at some point.…”

Section: Discussionsupporting

confidence: 71%

“…Of note, poliovirus variants selected for resistance to soluble poliovirus cell receptors, despite their reduced binding to HeLa cells, did not differ significantly from the wild-type virus with regard to the kinetics of viral replication in vitro or neurovirulence for mice (12). Although there are conflicting data on the ability of HRVs selected for resistance to a capsid-binding agent, chalcone Ro 09-0410, to grow in cell cultures (1,21), one resistant HRV-2 variant was found to have significantly reduced infectivity for humans (20). Further characterization of the sICAM-1-resistant phenotype, including its ability to replicate in human cell lines and respiratory cell epithelium, is warranted.…”

Section: Discussionmentioning

confidence: 97%

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In vitro selection of human rhinovirus relatively resistant to soluble intercellular adhesion molecule-1

Arruda

Crump

Hayden

1994

Antimicrob Agents Chemother

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Variants of human rhinovirus serotype 39 (HRV-39) relatively resistant to inhibition by soluble intercellular adhesion molecule-1 (sICAM-1) were selected by serial passages in HeLa or WI-38 cells in the presence of sICAM-1. Moderate resistance (four-to fivefold increases in 50%v effective inhibitory concentrations [EC50s]) was observed after the second passage in HeLa cells and remained constant during six further passages in the presence of 10 ,ug of sICAM-1 per ml. A 7-to 17-fold increase in EC50s was observed in WI-38 cells during passage with 10 ,ug/ml, and reversion to a nonresistant phenotype was not observed after four passages in the absence of sICAM-1. Resistance of a higher degree was obtained by passaging HRV-39 in the presence of 100 pg of sICAM-1 per ml in HeLa cells (30-fold EC50 increase). The sICAM-1-resistant phenotype was estimated to constitute 1 in 104 to 1 in 105 PFU of a nonexposed HRV-39 population. Low to moderate levels of resistance to sICAM-1 inhibition emerge readily during in vitro passage in the presence of sICAM-1 and appear to be phenotypically stable.The cell receptor for human rhinoviruses (HRVs) of the major receptor group has been identified as intercellular adhesion molecule-i (ICAM-1) (8,18,19), and recombinant soluble forms of ICAM-1 (sICAM-1) have been shown to inhibit HRV replication in vitro (3,9,14). One form of sICAM-1 (14) inhibits the replication of 88 of the 90 numbered HRV serotypes of the major receptor group, with 50% effective inhibitory concentrations (EC50s) ranging from 0.1 to 41.1 ,ug/ml (5). Because the virus receptor binding site appears to be conserved, it has been postulated that a viral mutation which confers resistance to inhibition by a soluble cell receptor molecule might be lethal, unless attachment by an alternative receptor is possible (14). However, poliovirus mutants resistant to the antiviral effects of the poliovirus soluble cell receptor have been isolated (12). Furthermore, these resistant variants maintained the same receptor specificity as the original poliovirus, as determined by a receptor blockade with an antireceptor monoclonal antibody, and appeared to be as virulent as the wild-type virus following mouse inoculation (12).This report describes the selection of variants of HRV serotype 39 (HRV-39), a major receptor group HRV readily inhibited by sICAM-1 in cell cultures and human adenoid explants (3), that are moderately resistant to the antiviral action of sICAM-1 in vitro. We have also estimated the frequency with which such resistant variants occur in a native population of HRV-39. .). Growth and maintenance media were the same as those previously described (3). sICAM-1, prepared and purified as previously described (14, 16), was kindly furnished by Boehringer Ingelheim Pharmaceuticals (Ridgefield, Conn.). MATERIALS AND METHODSSelection of resistance to sICAM-1. Isolation of HRV-39 resistant to sICAM-1 was achieved by end-point titration in the presence of sICAM-1. In brief, serial log1o dilutions of HRV-39, 107 50% tissue culture ...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 97%

In vitro selection of human rhinovirus relatively resistant to soluble intercellular adhesion molecule-1

Arruda

Crump

Hayden

1994

Antimicrob Agents Chemother

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“…In a study conducted with laboratory-isolated drug-resistant mutants of RVs, infectivity of the virus was reduced significantly (Yasin et al, 1990). This result is consistent with laboratory observations with drug-resistant coxsackievirus B3, which showed a marked reduction in virulence in mice compared with wild-type virus .…”

Section: Drug Resistancesupporting

confidence: 77%

Antiviral Therapy for Enteroviruses and Rhinoviruses

Rotbart

2000

Antivir Chem Chemother

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The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infection of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens -the rhinoviruses, the enteroviruses (including polioviruses, coxsackieviruses and echoviruses) and the hepatoviruses (including hepatitis A virus). This article will focus on the rhinoviruses and enteroviruses, agents for which substantial effort has been expended, and recent successes reported, toward the development of safe and effective antiviral therapy.

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“…We conclude by discussing a specific case study: the treatment of picornaviruses with pleconaril (Yasin et al 1990;Pevear et al 1999;Hayden et al 2003). Picornaviruses, which include enteroviruses and rhinoviruses, are the most ubiquitous pathogens of humans.…”

Section: Discussionmentioning

confidence: 99%

Immune responses and the emergence of drug–resistant virus strainsin vivo

Wodarz

Lloyd

2004

Proc. R. Soc. Lond. B

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The treatment of viral infections using antiviral drugs has had a significant public health benefit in the setting of human immunodeficiency virus (HIV) infection, and newly developed drugs offer potential benefits in the management of other viral infections, including acute self-limiting infections such as influenza and picornaviruses (including the rhinoviruses that are responsible for a large proportion of 'common colds'). A serious concern with such treatments is that they may lead to the selection of drug-resistant strains. This has been a significant problem in the case of HIV infection. Existing mathematical-modelling studies of drug resistance have focused on the interactions between virus, target cells and infected cells, ignoring the impact of immune responses. Here, we present a model that explores the role of immune responses in the rise of drug-resistant mutants in vivo. We find that drug resistance is unlikely to be a problem if immune responses are maintained above a threshold level during therapy. Alternatively, if immune responses decline at a fast rate and fall below a threshold level during treatment (indicating impaired immunity), the rise of drug-resistant mutants is more likely. This indicates an important difference between HIV, which impairs immunity and for which immune responses have been observed to vanish during treatment, and viral infections such as influenza and rhinoviruses, for which such immune impairment is not present. Drug resistance is much more likely to be a problem in HIV than in acute and self-limiting infections.

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Pathogenicity for humans of human rhinovirus type 2 mutants resistant to or dependent on chalcone Ro 09-0410

Cited by 20 publications

References 15 publications

In vitro selection of human rhinovirus relatively resistant to soluble intercellular adhesion molecule-1

In vitro selection of human rhinovirus relatively resistant to soluble intercellular adhesion molecule-1

Antiviral Therapy for Enteroviruses and Rhinoviruses

Immune responses and the emergence of drug–resistant virus strainsin vivo

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