Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232

• Published in: PloS one Vol. 18; no. 1; p. e0280568
• Main Authors: Smith, Robert A, Raugi, Dana N, Nixon, Robert S, Song, Jennifer, Seydi, Moussa, Gottlieb, Geoffrey S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18-01-2023; Public Library of Science (PLoS)
• Subjects: Anti-HIV Agents - pharmacology; Antiviral agents; Biology and Life Sciences; Capsid Proteins - genetics; Cell culture; Clinical trials; Cloning; Computer software industry; Drug dosages; Drug therapy; Engineering and Technology; gag Gene Products, Human Immunodeficiency Virus - genetics; Gag protein; Health aspects; HIV; HIV (Viruses); HIV Seropositivity; HIV testing; HIV-2 - genetics; Human immunodeficiency virus; Humans; Inhibitors; Maturation; Medicine and Health Sciences; Peptides; Peptides - pharmacology; Pharmaceutical research; Phenotypes; Proteins; Proteolysis; Research and Analysis Methods; Scientific equipment and supplies industry; Simian immunodeficiency virus; Testing; Triterpenes - pharmacology; Viral drug resistance; Virions; Virus Replication; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0280568

GSK2838232 (GSK232) is a novel maturation inhibitor that blocks the proteolytic cleavage of HIV-1 Gag at the junction of capsid and spacer peptide 1 (CA/SP1), rendering newly-formed virions non-infectious. To our knowledge, GSK232 has not been tested against HIV-2, and there are limited data regarding the susceptibility of HIV-2 to other HIV-1 maturation inhibitors. To assess the potential utility of GSK232 as an option for HIV-2 treatment, we determined the activity of the compound against a panel of HIV-1, HIV-2, and SIV isolates in culture. GSK232 was highly active against HIV-1 isolates from group M subtypes A, B, C, D, F, and group O, with IC50 values ranging from 0.25-0.92 nM in spreading (multi-cycle) assays and 1.5-2.8 nM in a single cycle of infection. In contrast, HIV-2 isolates from groups A, B, and CRF01_AB, and SIV isolates SIVmac239, SIVmac251, and SIVagm.sab-2, were highly resistant to GSK232. To determine the role of CA/SP1 in the observed phenotypes, we constructed a mutant of HIV-2ROD9 in which the sequence of CA/SP1 was modified to match the corresponding sequence found in HIV-1. The resulting variant was fully susceptible to GSK232 in the single-cycle assay (IC50 = 1.8 nM). Collectively, our data indicate that the HIV-2 and SIV isolates tested in our study are intrinsically resistant to GSK232, and that the determinants of resistance map to CA/SP1. The molecular mechanism(s) responsible for the differential susceptibility of HIV-1 and HIV-2/SIV to GSK232 require further investigation.