Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are effective against both wild-type (WT) HIV-1 integrase and many of the first-generation INSTI-resistant mutants. The emergence of resistance to these new second-generation INSTIs has been minimal, which has resulted in alternative treatment strategies for HIV-1 patients. Moreover, because of their high antiviral potencies and, in some cases, their bioavailability profiles, INSTIs will probably have prominent roles in pre-exposure prophylaxis (PrEP). Herein, we review the current state of the clinically relevant INSTIs and discuss the future outlook for this class of antiretrovirals.

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Comparable In Vitro Activities of Second-Generation HIV-1 Integrase Strand Transfer Inhibitors (INSTIs) on HIV-1 Clinical Isolates with INSTI Resistance Mutations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01717-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 1

Author(s):

Francesco Saladini ◽

Alessia Giannini ◽

Adele Boccuto ◽

Filippo Dragoni ◽

Alice Appendino ◽

...

Keyword(s):

First Generation ◽

Second Generation ◽

Cross Resistance ◽

Strand Transfer ◽

Resistance Mutations ◽

Genetic Barrier ◽

Integrase Strand Transfer Inhibitors ◽

Comparable Activity ◽

Hiv 1

ABSTRACT Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC, and CAB demonstrated a comparable activity on a panel of INSTI-resistant strains isolated from patients exposed to RAL, EVG, and/or DTG, with a significantly reduced susceptibility only with the pathway Q148H/K/R plus one to two additional INSTI mutations.

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Impact of HIV-1 Integrase L74F and V75I Mutations in a Clinical Isolate on Resistance to Second-Generation Integrase Strand Transfer Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00315-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 12

Author(s):

Atsuko Hachiya ◽

Karen A. Kirby ◽

Yoko Ido ◽

Urara Shigemi ◽

Masakazu Matsuda ◽

...

Keyword(s):

Clinical Isolate ◽

Virological Failure ◽

Rational Design ◽

Clinical Case ◽

First Generation ◽

Second Generation ◽

Strand Transfer ◽

Integrase Strand Transfer Inhibitors ◽

Mutation Pattern ◽

Hiv 1

ABSTRACT A novel HIV-1 integrase mutation pattern, L74F V75I, which conferred resistance to first-generation integrase strand transfer inhibitors (INSTIs), was identified in a clinical case with virological failure under a raltegravir-based regimen. Addition of L74F V75I to N155H or G140S Q148H increased resistance levels to the second-generation INSTIs dolutegravir (>385- and 100-fold, respectively) and cabotegravir (153- and 197-fold, respectively). These findings are important for the development of an accurate system for interpretation of INSTI resistance and the rational design of next-generation INSTIs.

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Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b01037 ◽

2015 ◽

Vol 58 (20) ◽

pp. 8154-8165 ◽

Cited By ~ 19

Author(s):

Izzat T. Raheem ◽

Abbas M. Walji ◽

Daniel Klein ◽

John M. Sanders ◽

David A. Powell ◽

...

Keyword(s):

Second Generation ◽

Strand Transfer ◽

Integrase Strand Transfer Inhibitors ◽

Hiv 1

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Inhibition of HTLV-1 Infection by HIV-1 First- and Second-Generation Integrase Strand Transfer Inhibitors

Frontiers in Microbiology ◽

10.3389/fmicb.2019.01877 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Michał S. Barski ◽

Jordan J. Minnell ◽

Goedele N. Maertens

Keyword(s):

Second Generation ◽

Strand Transfer ◽

Integrase Strand Transfer Inhibitors ◽

First And Second Generation ◽

Hiv 1

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Correction to Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b01957 ◽

2015 ◽

Vol 59 (1) ◽

pp. 486-486 ◽

Cited By ~ 1

Author(s):

Izzat T. Raheem ◽

Abbas M. Walji ◽

Daniel Klein ◽

John M. Sanders ◽

David A. Powell ◽

...

Keyword(s):

Second Generation ◽

Strand Transfer ◽

Integrase Strand Transfer Inhibitors ◽

Hiv 1

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Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection

Scientific Reports ◽

10.1038/s41598-021-90678-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna Prats ◽

Ignacio Martínez-Zalacaín ◽

Beatriz Mothe ◽

Eugènia Negredo ◽

Núria Pérez-Álvarez ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Integrase Inhibitor ◽

Strand Transfer ◽

Cognitive Differences ◽

Integrase Strand Transfer Inhibitors ◽

Initiation Of Therapy ◽

Main Component ◽

Living With Hiv ◽

The Impact ◽

Hiv 1

AbstractIntegrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

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Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor

Journal of Virology ◽

10.1128/jvi.01164-10 ◽

2010 ◽

Vol 84 (18) ◽

pp. 9210-9216 ◽

Cited By ~ 63

Author(s):

Tamara Bar-Magen ◽

Richard D. Sloan ◽

Daniel A. Donahue ◽

Björn D. Kuhl ◽

Alexandra Zabeida ◽

...

Keyword(s):

Viral Replication ◽

First Generation ◽

Second Generation ◽

Integrase Inhibitor ◽

Replication Capacity ◽

Strand Transfer ◽

Viral Replication Capacity ◽

Transfer Inhibitor ◽

Potential Basis

ABSTRACT MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer “off” rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg2+ binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.

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