ArticleRetrovirology2015
A single-residue change in the HIV-1 V3 loop associated with maraviroc resistance impairs CCR5 binding affinity while increasing replicative capacity.
Article in Retrovirology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- HIV-1 subtype C predicted co-receptor tropism in Africa: an individual sequence level meta-analysis.AIDS research and therapy · 2020Pooled it
- Targeting of specific CCR5-G protein complexes underlies biased signaling by HIV-1 envelope glycoproteins.Cell communication and signaling : CCS · 2025Article
- Immunoinformatic-driven design and evaluation of multi-epitope mRNA vaccine targeting HIV-1 gp120.Frontiers in immunology · 2025Article
- High concentrations of Maraviroc do not alter immunological and metabolic parameters of CD4 T cells.Scientific reports · 2024Article
- The chemokine receptor CCR5: multi-faceted hook for HIV-1.Retrovirology · 2024Review
- The Characteristics of the HIV-1 Env Glycoprotein Are Linked With Viral Pathogenesis.Frontiers in microbiology · 2022Article
- Modeling of CCR5 Recognition by HIV-1 gp120: How the Viral Protein Exploits the Conformational Plasticity of the Coreceptor.Viruses · 2021Article
- Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis.PLoS pathogens · 2021Article
- A Founder Effect Led Early SARS-CoV-2 Transmission in Spain.Journal of virology · 2021Article
- Extra-Low-Frequency Pulse Stimulated Conformational Change in Blood-Cell Proteins and Consequent Immune Activity Transformation.IEEE journal of translational engineering in health and medicine · 2020Article
- Tuberculosis Exacerbates HIV-1 Infection through IL-10/STAT3-Dependent Tunneling Nanotube Formation in Macrophages.Cell reports · 2019Article
- CCR5 structural plasticity shapes HIV-1 phenotypic properties.PLoS pathogens · 2018Article
- Phenotypic co-receptor tropism and Maraviroc sensitivity in HIV-1 subtype C from East Africa.Scientific reports · 2018Article
- The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1.Scientific reports · 2017Article
- Recent Insights into the HIV/AIDS Pandemic.Microbial cell (Graz, Austria) · 2016Review
- Buffering deleterious polymorphisms in highly constrained parts of HIV-1 envelope by flexible regions.Retrovirology · 2016Article
- A Review of Functional Motifs Utilized by Viruses.Proteomes · 2016Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMaraviroc (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.
resultsHere, 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.
conclusionThese 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.
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