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Volume 17
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10.3390/v17010121
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Article

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

by
Steven J. Smith
1,*,
Xue Zhi Zhao
1,
Stephen H. Hughes
2 and
Terrence R. Burke, Jr.
1
1
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
2
HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
*
Author to whom correspondence should be addressed.
Viruses 2025, 17(1), 121; https://doi.org/10.3390/v17010121
Submission received: 4 December 2024 / Revised: 13 January 2025 / Accepted: 14 January 2025 / Published: 16 January 2025
(This article belongs to the Collection Efficacy and Safety of Antiviral Therapy)
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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.
Keywords: integrase; resistance; potency; mutations; mutants integrase; resistance; potency; mutations; mutants

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MDPI and ACS Style

Smith, S.J.; Zhao, X.Z.; Hughes, S.H.; Burke, T.R., Jr. 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. Viruses 2025, 17, 121. https://doi.org/10.3390/v17010121

AMA Style

Smith SJ, Zhao XZ, Hughes SH, Burke TR Jr. 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. Viruses. 2025; 17(1):121. https://doi.org/10.3390/v17010121

Chicago/Turabian Style

Smith, Steven J., Xue Zhi Zhao, Stephen H. Hughes, and Terrence R. Burke, Jr. 2025. "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" Viruses 17, no. 1: 121. https://doi.org/10.3390/v17010121

APA Style

Smith, S. J., Zhao, X. Z., Hughes, S. H., & Burke, T. R., Jr. (2025). 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. Viruses, 17(1), 121. https://doi.org/10.3390/v17010121

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