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Comparative Analyses of Antiviral Potencies of Second-Generation Integrase Strand Transfer Inhibitors (INSTIs) and the Developmental Compound 4d Against a Panel of Integrase Quadruple Mutants

  1. Author:
    Smith,Steven [ORCID]
    Zhao,Xuezhi [ORCID]
    Hughes,Stephen [ORCID]
    Burke,Terrence [ORCID]

  2. Author Address

    Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.,
    1. Year: 2025
    2. Date: Jan 16
    3. Epub Date: 2025 01 16
  2. Journal: Viruses
    1. 17
    2. 1
  4. Type of Article: Article
  1. Abstract:

    Second-generation integrase strand transfer inhibitors (INSTIs) are strongly recommended for people living with HIV-1 (PLWH). The emergence of resistance to second-generation INSTIs has been infrequent and has not yet been a major issue in high-income countries. However, the delayed rollouts of these INSTIs in low- to middle-income countries during the COVID-19 pandemic combined with increased transmission of drug-resistant mutants worldwide are leading to an increase in INSTI resistance. Herein, we evaluated the antiviral potencies of our lead developmental INSTI 4d and the second-generation INSTIs dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) against a panel of IN quadruple mutants. The mutations are centered around G140S/Q148H, including positions L74, E92, and T97 combined with E138A/K/G140S/Q148H. All of the tested INSTIs lose potency against these IN quadruple mutants compared with the wild-type IN. In single-round infection assays, compound 4d retained higher antiviral potencies (EC50 values) than second-generation INSTIs against a subset of quadruple mutants. These findings may advance understanding of mechanisms that contribute to resistance and, in so doing, facilitate development of new INSTIs with improved antiviral profiles.

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External Sources

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  2. DOI: 10.3390/v17010121
  3. PMID: 39861910
  4. PMCID: PMC11768864
  5. PII : v17010121

Library Notes

  1. Fiscal Year: FY2024-2025
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