HIV Protease Inhibitor Resistance

Wensing, Annemarie M. J.; Fun, Axel; Nijhuis, Monique

doi:10.1007/978-1-4939-0667-3_28-1

Cited by 3 publications

(3 citation statements)

References 194 publications

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“…Secondary mutations, on the other hand, are additional mutations that tend to accumulate under selection pressure and may either intensify or alleviate effects of the primary mutations. It is not uncommon to encounter 1-6 amino acid insertions at various sites in the viral protease sequence during the course of PI-based therapy, which tend to alleviate selection pressure and improve viral replication [48,49].…”

Section: Hiv-1 Protease Inhibitor-associated Mutations and The Mechan...mentioning

confidence: 99%

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Mótyán

Mahdi

Hoffka

et al. 2022

IJMS

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Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of the most devastating pandemics of recent times. The lack of potent novel antivirals had led to global health crises; however, emergence and approval of potent inhibitors of the viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in the therapeutic front but also in the context of prophylaxis against the infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, and lessons learnt from previous and currently ongoing pandemics have taught us that these viruses can easily escape selection pressure through mutation of vital target amino acid residues in monotherapeutic settings. In this paper, we review nirmatrelvir and its binding to SARS-CoV-2 Mpro and draw a comparison to inhibitors of HIV protease that were rendered obsolete by emergence of resistance mutations, emphasizing potential pitfalls in the design of inhibitors that may be of important relevance to the long-term use of novel inhibitors against SARS-CoV-2.

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Section: Hiv-1 Protease Inhibitor-associated Mutations and The Mechan...mentioning

confidence: 99%

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Mótyán

Mahdi

Hoffka

et al. 2022

IJMS

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“…Resistance mutations differ across various codons in different HIV-1 subtypes. Codons 33,34,58,63,73,71,77, and 84 are more commonly associated with resistance mutations in subtype B viruses compared to subtype F or C viruses, whereas mutations at codons 20, 36, and 89 are not very common [67]. In subtype C virions, resistance mutations occur with higher frequency at codons 20, 36, 89, and 93, while being less common at codons 10, 30, 43, 46, and 74 [67].…”

Section: Mechanism Of Resistance To Pismentioning

confidence: 96%

“…Subsequent exposure to selective drug pressure results in the emergence of secondary resistance substitutions, which ultimately enhance viral fitness. The identified mutations induce changes in the activities of the integrase protein [71].…”

Section: Mechanism Of Resistance To Instismentioning

confidence: 99%

Current ARTs, Virologic Failure, and Implications for AIDS Management: A Systematic Review

Foka

Mufhandu

2023

Viruses

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Antiretroviral therapies (ARTs) have revolutionized the management of human immunodeficiency virus (HIV) infection, significantly improved patient outcomes, and reduced the mortality rate and incidence of acquired immunodeficiency syndrome (AIDS). However, despite the remarkable efficacy of ART, virologic failure remains a challenge in the long-term management of HIV-infected individuals. Virologic failure refers to the persistent detectable viral load in patients receiving ART, indicating an incomplete suppression of HIV replication. It can occur due to various factors, including poor medication adherence, drug resistance, suboptimal drug concentrations, drug interactions, and viral factors such as the emergence of drug-resistant strains. In recent years, extensive efforts have been made to understand and address virologic failure in order to optimize treatment outcomes. Strategies to prevent and manage virologic failure include improving treatment adherence through patient education, counselling, and supportive interventions. In addition, the regular monitoring of viral load and resistance testing enables the early detection of treatment failure and facilitates timely adjustments in ART regimens. Thus, the development of novel antiretroviral agents with improved potency, tolerability, and resistance profiles offers new options for patients experiencing virologic failure. However, new treatment options would also face virologic failure if not managed appropriately. A solution to virologic failure requires a comprehensive approach that combines individualized patient care, robust monitoring, and access to a range of antiretroviral drugs.

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Inhibition of HIV‐1 Protease by Carpobrotus edulis (L.)

Omoruyi

Ighodaro

Afolayan

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Carpobrotus edulis (L.) is a plant commonly found in the Eastern Cape Province of South Africa and is used for the general treatment of infections relating to the human immunodeficiency virus (HIV). HIV-1 protease plays an important role during HIV replication and maturation to its infectious form, and therefore inhibition of the enzyme is one of the main focus areas in drug development. The inhibitory effect of a water extract of C. edulis leaves against HIV-1 protease activity was determined using the SensoLyte® 520 HIV-1 protease assay fluorimetric kit and employing a HiLyte Fluor™488/QXL™520 fluorescence resonance energy transfer (FRET) peptide. Cytotoxicity of the extract towards HeLa Chang cell lines was determined using an in vitro MTT assay, and the phytochemical profile of the extract was determined with FT-IR and LC-MS. HIV-1 protease activity was inhibited 83.06% (IC50 1.6 mg/ml) (p<0.0001) by the pepstatin A inhibitor control. Treatment with all C. edulis extract concentrations (16, 1.6, 0.16, and 0.016 mg/ml) inhibited HIV-1 protease activity significantly (p<0.0001) in a typical dose response manner. With regards to cytotoxicity, the negative controls containing untreated HeLa Chang cells exhibited high formazan formation rates in contrast with the positive controls, containing curcumin, which reduced formazan formation significantly (p<0.001), exhibiting cytotoxicity towards the cells. There was no significant (p>0.05) difference in the formazan formation rates between the negative controls and 1, 0.5, 0.125, 0.065, 0.031, and 0.015 mg/ml plant extract, confirming no toxicity of C. edulis extracts towards HeLa Chang cells. Major functional phytochemical compounds identified included alcohols, phenols, alkanes, amines, carboxylic acids, and esters. LC-ESI-TOF/MS analysis revealed the putative identities of main compounds present in the aqueous leaves extract, including some that contribute to its anti-HIV-1 protease action.

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HIV Protease Inhibitor Resistance

Cited by 3 publications

References 194 publications

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Current ARTs, Virologic Failure, and Implications for AIDS Management: A Systematic Review

Inhibition of HIV‐1 Protease by Carpobrotus edulis (L.)

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