Viral quasispecies and the problem of vaccine-escape and drug-resistant mutants

Domingo, Esteban; Menéndez‐Arias, Luis; Quiñones‐Mateu, Miguel E.; Holguín, África; Gutiérrez-Rivas, Mónica; Martı́nez, Miguel Ángel; Quer, Josep; Novella, Isabel S.; Holland, John J.

doi:10.1007/978-3-0348-8861-5_4

Cited by 50 publications

(53 citation statements)

References 181 publications

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“…Ligands that cause internalization of CXCR4 (Amara et al, 1997) or CCR5 (Simmons et al, 1997) have been shown to protect against HIV-1 infection in vitro. Selective removal of chemokine receptors from the cell surface could be superior to blocking chemokine receptor interaction with HIV viral coat proteins because it would prevent the possible rapid emergence of resistant HIV variants through therapeutic pressure and mutation (Domingo et al, 1997). Receptor dimerization may also generate therapeutic targets with unique pharmacology and signaling characteristics.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling

Maudsley¹,

Martin²,

Luttrell³

2005

J Pharmacol Exp Ther

173

172

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The modulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes the single most important therapeutic target in medicine. Drugs acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two-state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and "texture" than previously appreciated. Signal diversity arises from numerous factors, among which are the ability of receptors to adopt multiple "active" states with different effector-coupling profiles; the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking; the dissociation of receptor "activation" from desensitization and internalization; and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confer signal preorganization, efficiency, and specificity. In this context, the concept of agonist-selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of active receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands possessing increased specific efficacy and attenuated side effects may become the standard mode of drug development.The heptahelical G protein-coupled receptors (GPCRs) constitute the most diverse form of transmembrane signaling protein. An estimated 1% of the mammalian genome encodes GPCRs, and about 450 of the approximately 950 predicted human GPCRs are expected to be receptors for endogenous ligands (Takeda et al., 2002). GPCRs detect an extraordinarily diverse set of stimuli in the external environment, from photons of light and ions to small molecule neurotransmitters, peptides, glycoproteins, and phospholipids. In addition, nearly 40% of all current therapeutics target GPCRs (Brink et al., 2004).The mechanism by which GPCRs transduce extracellular messages into intracellular cellular responses was initially envisioned as a simple linear model in which agonist binding promotes transition of the receptor from an "off" to an "on" state capable of engaging heterotrimeric guanine nucleotidebinding (G) proteins, whose dissociated G␣ and G␤␥ subunits

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Section: Therapeutic Implicationsmentioning

confidence: 99%

The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling

Maudsley¹,

Martin²,

Luttrell³

2005

J Pharmacol Exp Ther

173

172

View full text Add to dashboard Cite

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“…RNA viruses count among the most plastic organisms on Earth and are an iconic example of populations persistently escaping the action of antiviral drugs (1,2). Drugs exert constant selection pressures on viral populations, and as such, the question is not whether a resistant form of the virus will appear but when it will occur.…”

mentioning

confidence: 99%

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

Iranzo

Perales

Domingo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The continuous emergence of drug-resistant viruses is a major obstacle for the successful treatment of viral infections, thus representing a persistent spur to the search for new therapeutic strategies. Among them, multidrug treatments are currently at the forefront of pharmaceutical, clinical, and computational investigation. Still, there are many unknowns in the way that different drugs interact among themselves and with the pathogen that they aim to control. Inspired by experimental studies with picornavirus, here, we discuss the performance of sequential vs. combination therapies involving two dissimilar drugs: the mutagen ribavirin and an inhibitor of viral replication, guanidine. Because a systematic analysis of viral response to drug doses demands a precious amount of time and resources, we present and analyze an in silico model describing the dynamics of the viral population under the action of the two drugs. The model predicts the response of the viral population to any dose combination, the optimal therapy to be used in each case, and the way to minimize the probability of appearance of resistant mutants. In agreement with the theoretical predictions, in vitro experiments with foot-and-mouth disease virus confirm that the suitability of simultaneous or sequential administration depends on the drug doses. In addition, intrinsic replicative characteristics of the virus (e.g., replication through RNA only or a DNA intermediate) play a key role to determine the appropriateness of a sequential or combination therapy. Knowledge of several model parameters can be derived by means of few, simple experiments, such that the model and its predictions can be extended to other viral systems.population dynamics | antiviral design | viral quasispecies | mutation | viral adaptation

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“…Viral quasispecies constitute large reservoirs of variants that are the basis for the extreme adaptability and rapid evolution of many RNA viruses. The quasispecies concept and its biological implications are increasingly being taken into account in the development of preventive measures and therapies against diseases caused by RNA viruses (20,21). The high heterogeneity and adaptability of RNA virus populations are partly due to the high mutation rates during RNA replication in the absence of proofreading mechanisms and mismatch repair systems.…”

mentioning

confidence: 99%

“…Unfortunately, the quasispecies nature of RNA virus populations may severely hamper the effectiveness of both vaccination and passive immunotherapy. RNA viruses can easily evade the action of neutralizing antibodies in vitro through the rapid selection from their heterogeneous populations of MAb-resistant (MAR) mutants with amino acid substitutions at the corresponding epitopes (21). In vivo, the emergence of escape mutants in individuals either vaccinated or treated with passive immunotherapy has also been documented (10,14,26,48,50,57).…”

mentioning

confidence: 99%

High Mutant Frequency in Populations of a DNA Virus Allows Evasion from Antibody Therapy in an Immunodeficient Host

López-Bueno

Mateu

Almendral

2003

J Virol

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Viral quasispecies and the problem of vaccine-escape and drug-resistant mutants

Cited by 50 publications

References 181 publications

The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling

The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

High Mutant Frequency in Populations of a DNA Virus Allows Evasion from Antibody Therapy in an Immunodeficient Host

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