ArticleProceedings of the National Academy of Sciences of the United States of America2023
Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope formation and substantially delays or eliminates viral rebound.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Mechanisms of HIV-1 assembly, release and maturation.Nature reviews. Microbiology · 2026Review
- The K247 ubiquitination site of the Newcastle disease virus M protein enhances viral budding to facilitate rapid exploitation of host cell sphingolipid metabolites.Poultry science · 2026Article
- Remodeling of Metabolic and Secretory Organelles During Oncogenic and Oncomodulatory Viral Infections.Viruses · 2026Review
- The potential of academic drug discovery: successes and challenges.Expert opinion on drug discovery · 2025Article
- Oxidative Stress in HIV-Associated Neurodegeneration: Mechanisms of Pathogenesis and Therapeutic Targets.International journal of molecular sciences · 2025Review
- Neutral sphingomyelinase 2: A promising drug target for CNS disease.Advances in pharmacology (San Diego, Calif.) · 2025Review
- Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs.Pharmaceutics · 2024Article
- Review
- Significance of Cellular Lipid Metabolism for the Replication of Rotaviruses and Other RNA Viruses.Viruses · 2024Review
- Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration.Cells · 2024Review
- Lipidomics reveals the significance and mechanism of the cellular ceramide metabolism for rotavirus replication.Journal of virology · 2024Article
- Fighting nature with nature: antiviral compounds that target retroviruses.Archives of microbiology · 2024Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Although HIV-1 Gag is known to drive viral assembly and budding, the precise mechanisms by which the lipid composition of the plasma membrane is remodeled during assembly are incompletely understood. Here, we provide evidence that the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) interacts with HIV-1 Gag and through the hydrolysis of sphingomyelin creates ceramide that is necessary for proper formation of the viral envelope and viral maturation. Inhibition or depletion of nSMase2 resulted in the production of noninfectious HIV-1 virions with incomplete Gag lattices lacking condensed conical cores. Inhibition of nSMase2 in HIV-1-infected humanized mouse models with a potent and selective inhibitor of nSMase2 termed PDDC [phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2, 6-dimethylimidazo[1,2-b]pyridazin-8-yl) pyrrolidin-3-yl)-carbamate] produced a linear reduction in levels of HIV-1 in plasma. If undetectable plasma levels of HIV-1 were achieved with PDDC treatment, viral rebound did not occur for up to 4 wk when PDDC was discontinued. In vivo and tissue culture results suggest that PDDC selectively kills cells with actively replicating HIV-1. Collectively, this work demonstrates that nSMase2 is a critical regulator of HIV-1 replication and suggests that nSMase2 could be an important therapeutic target with the potential to kill HIV-1-infected cells.
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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.