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


Autoři: Ira Dicker aff001;  Sharon Zhang aff001;  Neelanjana Ray aff002;  Brett R. Beno aff003;  Alicia Regueiro-Ren aff004;  Samit Joshi aff005;  Mark Cockett aff001;  Mark Krystal aff001;  Max Lataillade aff005
Působiště autorů: Department of HIV Discovery, ViiV Healthcare, Branford, Connecticut, United States of America aff001;  Department of Early Development, Bristol-Myers Squibb Research and Development, Princeton, New Jersey, United States of America aff002;  Department of Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, United States of America aff003;  Department of Chemistry Bristol-Myers Squibb Research and Development, Wallingford Connecticut, United States of America aff004;  Department of Early Development, ViiV Healthcare, Branford, Connecticut, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224076

Souhrn

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.

Klíčová slova:

HIV – HIV-1 – Monomers – Proteases – Substitution mutation – Viral packaging – Viral replication – Amino acid substitution


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