Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study

Autor:	Max Lataillade, Samit R Joshi, Brett R. Beno, Ira B. Dicker, Mark Krystal, Sharon Zhang, Neelanjana Ray, Mark I. Cockett, Alicia Regueiro-Ren
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	RNA viruses Peptide Pathology and Laboratory Medicine Biochemistry Viral Packaging Immunodeficiency Viruses Medicine and Health Sciences Amino Acids chemistry.chemical_classification 0303 health sciences Multidisciplinary Organic Compounds Monomers Proteases Amino acid Enzymes Chemistry Capsid Medical Microbiology Viral Pathogens Viruses Physical Sciences Medicine Pathogens Binding domain Research Article Substitution Mutation Science Microbiology 03 medical and health sciences Cyclophilin A Virology Retroviruses Genetics Microbial Pathogens 030304 developmental biology Biology and life sciences 030306 microbiology Maturation inhibitor Lentivirus Organic Chemistry Organisms Chemical Compounds HIV Proteins Polymer Chemistry Molecular biology In vitro Viral Replication chemistry Viral replication Amino Acid Substitution Mutation HIV-1 Enzymology
Zdroj:	PLoS ONE PLoS ONE, Vol 14, Iss 10, p e0224076 (2019)
ISSN:	1932-6203 3532-3795
Popis:	GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f6a0d0dbc6b37d67c1283483e13ea1e0 http://europepmc.org/articles/PMC6797179 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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