Show simple item record

dc.contributor.authorGarcia-Perez, Javier 
dc.contributor.authorStaropoli, Isabelle
dc.contributor.authorAzoulay, Stéphane
dc.contributor.authorHeinrich, Jean-Thomas
dc.contributor.authorCascajero, Almudena 
dc.contributor.authorColin, Philippe
dc.contributor.authorLortat-Jacob, Hugues
dc.contributor.authorArenzana-Seisdedos, Fernando
dc.contributor.authorAlcamí, José 
dc.contributor.authorKellenberger, Esther
dc.contributor.authorLagane, Bernard
dc.identifier.citationRetrovirology. 2015 Jun 18;12:50.es_ES
dc.description.abstractBACKGROUND: Maraviroc (MVC) is an allosteric CCR5 inhibitor used against HIV-1 infection. While MVC-resistant viruses have been identified in patients, it still remains incompletely known how they adjust their CD4 and CCR5 binding properties to resist MVC inhibition while preserving their replicative capacity. It is thought that they maintain high efficiency of receptor binding. To date however, information about the binding affinities to receptors for inhibitor-resistant HIV-1 remains limited. RESULTS: Here, we show by means of viral envelope (gp120) binding experiments and virus-cell fusion kinetics that a MVC-resistant virus (MVC-Res) that had emerged as a dominant viral quasispecies in a patient displays reduced affinities for CD4 and CCR5 either free or bound to MVC, as compared to its MVC-sensitive counterpart isolated before MVC therapy. An alanine insertion within the GPG motif (G310_P311insA) of the MVC-resistant gp120 V3 loop is responsible for the decreased CCR5 binding affinity, while impaired binding to CD4 is due to sequence changes outside V3. Molecular dynamics simulations of gp120 binding to CCR5 further emphasize that the Ala insertion alters the structure of the V3 tip and weakens interaction with CCR5 ECL2. Paradoxically, infection experiments on cells expressing high levels of CCR5 also showed that Ala allows MVC-Res to use CCR5 efficiently, thereby improving viral fusion and replication efficiencies. Actually, although we found that the V3 loop of MVC-Res is required for high levels of MVC resistance, other regions outside V3 are sufficient to confer a moderate level of resistance. These sequence changes outside V3, however, come with a replication cost, which is compensated for by the Ala insertion in V3. CONCLUSION: These results indicate that changes in the V3 loop of MVC-resistant viruses can augment the efficiency of CCR5-dependent steps of viral entry other than gp120 binding, thereby compensating for their decreased affinity for entry receptors and improving their fusion and replication efficiencies. This study thus sheds light on unsuspected mechanisms whereby MVC-resistant HIV-1 could emerge and grow in treated patients.es_ES
dc.description.sponsorshipThis work was supported by Agence Nationale de la Recherche sur le SIDA (ANRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur, Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (Grant ANR-10- LABEX-62-IBEID), Instituto de Salud Carlos III (Intrasalud PI12/0056), the Spanish Ministry of Health (EC11-175) and Red de investigación en SIDA RD12/0017/0015 as part of the Plan Nacional R + D + I and cofinanced by ISCIII- Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER).es_ES
dc.relation.isversionofPublisher's versiones_ES
dc.subject.meshAnti-HIV Agentses_ES
dc.subject.meshHIV Envelope Protein gp120es_ES
dc.subject.meshMutant Proteinses_ES
dc.subject.meshProtein Bindinges_ES
dc.subject.meshReceptors, CCR5es_ES
dc.subject.meshReceptors, HIVes_ES
dc.subject.meshVirus Internalizationes_ES
dc.subject.meshVirus Replicationes_ES
dc.subject.meshDrug Resistance, Virales_ES
dc.subject.meshMutation, Missensees_ES
dc.titleA single-residue change in the HIV-1 V3 loop associated with maraviroc resistance impairs CCR5 binding affinity while increasing replicative capacityes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.contributor.funderAgence Nationale de Recherches sur le SIDA et les Hépatites Virales (France)es_ES
dc.contributor.funderInstitut National de la Santé et de la Recherche Médicale (France)es_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderRed Española de Investigación en SIDAes_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/ANR-10- LABEX-62-IBEIDes_ES

Files in this item

Acceso Abierto

This item appears in the following Collection(s)

Show simple item record

Atribución-NoComercial-CompartirIgual 4.0 Internacional
This item is licensed under a: Atribución-NoComercial-CompartirIgual 4.0 Internacional