Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research

Cobb, Denise; Smith, Nathan; Edagwa, Benson; McMillan, JoEllyn M

doi:10.1080/17425247.2020.1783233

Cited by 46 publications

(38 citation statements)

References 113 publications

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“…Limitations in delivery and failure to maintain therapeutic drug concentrations at sites of viral replication have also negatively impacted therapeutic outcomes. The absence of vaccines for chronic viral infections such as HIV and HCV has led to growing interest in long-acting (LA) formulations and devices aimed at improving patient adherence to therapy to minimize emergence of drug resistance [ 64 , 65 ].…”

Section: Hiv-1 Infection Pathogenesis Prevention and Antiretroviral Testingmentioning

confidence: 99%

Humanized Mice for Infectious and Neurodegenerative disorders

et al. 2021

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Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.

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Section: Hiv-1 Infection Pathogenesis Prevention and Antiretroviral Testingmentioning

confidence: 99%

Humanized Mice for Infectious and Neurodegenerative disorders

et al. 2021

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“…Long-acting formulations are appealing as a strategy to overcome the possibility of incomplete adherence. These have been reviewed previously by Edagwa et al 104 and more recently by Cobb et al 105 Currently, cabotegravir, rilpivirine, and islatravir are being studied as long-acting formulations in clinical trials. In the phase III LATTE-2 (Long-Acting Intramuscular Cabotegravir and Rilpivirine in Adults With HIV-1 Infection) study an intramuscular injection of cabotegravir (a novel INSTI) and rilpivirine every 4 and 8 weeks demonstrated noninferiority in suppressing plasma HIV RNA when compared with standard of care oral treatment regimens.…”

Section: Long-acting Hiv Treatmentmentioning

confidence: 99%

Pharmacology of HIV Cure: Site of Action

Devanathan

Cottrell

2021

Clin Pharma and Therapeutics

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Despite significant advances in HIV treatment over the past 30 years, critical barriers to an HIV cure persist. The HIV reservoir, defined at both the cellular and anatomical level, constitutes the main barrier to cure. While the mechanisms underlying the reservoir are not yet well understood, one theory to explain persistence at the anatomical level is that subtherapeutic exposure to antiretroviral therapy (ART) within certain tissue compartments permits ongoing replication. Characterizing ART pharmacology throughout the body is important in the context of these potential pharmacologic sanctuaries and for maximizing the probability of success with forthcoming cure strategies that rely on latency reversal and require ART to prevent reseeding the reservoir. In this review, we provide a comprehensive overview of ART and latency reversal agent distribution at the site of action for HIV cure (i.e., anatomical sites commonly associated with HIV persistence, such as lymphoid organs and the central nervous system). We also discuss methodologic approaches that provide insight into HIV cure pharmacology, including experimental design and advances within the computational, pharmaceutical, and analytical chemistry fields. The information discussed in this review will assist in streamlining the development of investigational cure strategies by providing a roadmap to ensure therapeutic exposure within the site of action for HIV cure.

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“…CA not only acts as the building block of the HIV-1 capsid core formation but also interacts with several host factors [ 4 , 5 , 6 , 7 , 8 ]. Small molecule agents with different chemotypes have been developed in recent years to disrupt the CA biological functions in the virus replication cycle [ 9 , 10 , 11 , 12 ]. Among them, GS-6207 exhibits antiviral activity at picomolar concentrations and is metabolically stable, which makes it highly promising as a potential long-acting agent for use in antiviral therapy [ 3 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Small molecule agents with different chemotypes have been developed in recent years to disrupt the CA biological functions in the virus replication cycle [ 9 , 10 , 11 , 12 ]. Among them, GS-6207 exhibits antiviral activity at picomolar concentrations and is metabolically stable, which makes it highly promising as a potential long-acting agent for use in antiviral therapy [ 3 , 11 , 12 , 13 ]. However, recent studies have identified several amino acid mutations in the CA binding site that confer drug resistance to GS-6207 [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

Sun

Levy

Kirby

et al. 2021

Viruses

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While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein−ligand steric clash, the I66 side chain in the M66I−GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein−ligand interaction that is largely responsible for the drug resistance against GS-6207.

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Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research

Cited by 46 publications

References 113 publications

Humanized Mice for Infectious and Neurodegenerative disorders

Humanized Mice for Infectious and Neurodegenerative disorders

Pharmacology of HIV Cure: Site of Action

Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

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