ArticleProceedings of the National Academy of Sciences of the United States of America2002
Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 220 papers.
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Who cites it
220 citing papers in PubMed, 403 citations in OpenAlex.
- HIV-1 clinical isolates resistant to CCR5 antagonists exhibit delayed entry kinetics that are corrected in the presence of drug.Journal of virology · 2012Trial
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- New Therapies and Strategies to Curb HIV Infections with a Focus on Macrophages and Reservoirs.Viruses · 2024Review
- The evolution of envelope function during coinfection with phylogenetically distinct human immunodeficiency virus.BMC infectious diseases · 2024Article
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- HIV-1 prehairpin intermediate inhibitors show efficacy independent of neutralization tier.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- 2022 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2022Article
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- HIV-1 cell-to-cell spread overcomes the virus entry block of non-macrophage-tropic strains in macrophages.PLoS pathogens · 2022Article
- Modular Lentiviral Vectors for Highly Efficient Transgene Expression in Resting Immune Cells.Viruses · 2021Article
- Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages.Virulence · 2020Review
- Identification and Characterization of a Small-Molecule Rabies Virus Entry Inhibitor.Journal of virology · 2020Article
- Next-generation direct-acting influenza therapeutics.Translational research : the journal of laboratory and clinical medicine · 2020Review
- The Tryptophan-Rich Motif of HIV-1 gp41 Can Interact with the N-Terminal Deep Pocket Site: New Insights into the Structure and Function of gp41 and Its Inhibitors.Journal of virology · 2019Article
- Mutations of Glu560 within HIV-1 Envelope Glycoprotein N-terminal heptad repeat region contribute to resistance to peptide inhibitors of virus entry.Retrovirology · 2019Article
- Strain-Dependent Activation and Inhibition of Human Immunodeficiency Virus Entry by a Specific PF-68742 Stereoisomer.Journal of virology · 2019Article
- 2019 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2019Article
- Article
- HIV-1 anchor inhibitors and membrane fusion inhibitors target distinct but overlapping steps in virus entry.The Journal of biological chemistry · 2019Article
160 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
HIV entry inhibitors include coreceptor antagonists and the fusion inhibitor T-20. T-20 binds the first helical region (HR1) in the gp41 subunit of the viral envelope (Env) protein and prevents conformational changes required for membrane fusion. HR1 appears to become accessible to T-20 after Env binds CD4, whereas coreceptor binding is thought to induce the final conformational changes that lead to membrane fusion. Thus, T-20 binds to a structural intermediate of the fusion process. Primary viruses exhibit considerable variability in T-20 sensitivity, and determinants outside of HR1 can affect sensitivity by unknown mechanisms. We studied chimeric Env proteins containing different V3 loop sequences and found that gp120coreceptor affinity correlated with T-20 and coreceptor antagonist sensitivity, with greater affinity resulting in increased resistance to both classes of entry inhibitors. Enhanced affinity resulted in more rapid fusion kinetics, reducing the time during which Env is sensitive to T-20. Reduced coreceptor expression levels also delayed fusion kinetics and enhanced virus sensitivity to T-20, whereas increased coreceptor levels had the opposite effect. A single amino acid change (K421D) in the bridging sheet region of the primary virus strain YU2 reduced affinity for CCR5 and increased T-20 sensitivity by about 30-fold. Thus, mutations in Env that affect receptor engagement and membrane fusion rates can alter entry inhibitor sensitivity. Because coreceptor expression levels are typically limiting in vivo, individuals who express lower coreceptor levels may respond more favorably to entry inhibitors such as T-20, whose effectiveness we show depends in part on fusion kinetics.
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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.