ArticlePloS one2011
Resistance to the CCR5 inhibitor 5P12-RANTES requires a difficult evolution from CCR5 to CXCR4 coreceptor use.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 41 citations in OpenAlex.
- Rational Engineering of a Sub-Picomolar HIV-1 Blocker.Viruses · 2022Article
- Novel small synthetic HIV-1 V3 crown variants: CCR5 targeting ligands.Journal of biochemistry · 2022Article
- Endogenous Peptide Inhibitors of HIV Entry.Advances in experimental medicine and biology · 2022Article
- Filling the Gaps in Antagonist CCR5 Binding, a Retrospective and Perspective Analysis.Frontiers in immunology · 2022Article
- An SAMT-247 Microbicide Provides Potent Protection against Intravaginal Simian Immunodeficiency Virus Infection of Rhesus Macaques, whereas an Added Vaccine Component Elicits Mixed Outcomes.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- CCR5 Inhibitors and HIV-1 Infection.Journal of AIDS and HIV treatment · 2019Article
- HIV Entry and Its Inhibition by Bifunctional Antiviral Proteins.Molecular therapy. Nucleic acids · 2018Review
- Functional Stability of HIV-1 Envelope Trimer Affects Accessibility to Broadly Neutralizing Antibodies at Its Apex.Journal of virology · 2017Article
- The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES.International journal of molecular sciences · 2017Article
- Article
- Stabilization and Sustained Release of HIV Inhibitors by Encapsulation in Silk Fibroin Disks.ACS biomaterials science & engineering · 2017Article
- The Expanding Therapeutic Perspective of CCR5 Blockade.Frontiers in immunology · 2017Review
- Development of peptide inhibitors of HIV transmission.Bioactive materials · 2016Review
- A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris.Protein expression and purification · 2016Article
- Viremic control and viral coreceptor usage in two HIV-1-infected persons homozygous for CCR5 Δ32.AIDS (London, England) · 2015Article
- Combination of the CCL5-derived peptide R4.0 with different HIV-1 blockers reveals wide target compatibility and synergic cobinding to CCR5.Antimicrobial agents and chemotherapy · 2014Article
- Review
- Using glycosaminoglycan/chemokine interactions for the long-term delivery of 5P12-RANTES in HIV prevention.Molecular pharmaceutics · 2013Article
- Peptide and protein-based inhibitors of HIV-1 co-receptors.Experimental biology and medicine (Maywood, N.J.) · 2013Review
- Prospects for treatment of latent HIV.Clinical pharmacology and therapeutics · 2013Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16-18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a "resistant" variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.