ArticleRetrovirology2012
Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity.
Article in Retrovirology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Fungal Proteases as Emerging Biocatalysts to Meet the Current Challenges and Recent Developments in Biomedical Therapies: An Updated Review.Journal of fungi (Basel, Switzerland) · 2022Review
- Nucleocapsid Protein Precursors NCp9 and NCp15 Suppress ATP-Mediated Rescue of AZT-Terminated Primers by HIV-1 Reverse Transcriptase.Antimicrobial agents and chemotherapy · 2020Article
- Amino-acid inserts of HIV-1 capsid (CA) induce CA degradation and abrogate viral infectivity: Insights for the dynamics and mechanisms of HIV-1 CA decomposition.Scientific reports · 2019Article
- Gag P2/NC and pol genetic diversity, polymorphism, and drug resistance mutations in HIV-1 CRF02_AG- and non-CRF02_AG-infected patients in Yaoundé, Cameroon.Scientific reports · 2017Article
- Gag-protease coevolution analyses define novel structural surfaces in the HIV-1 matrix and capsid involved in resistance to Protease Inhibitors.Scientific reports · 2017Article
- Genetic Changes in HIV-1 Gag-Protease Associated with Protease Inhibitor-Based Therapy Failure in Pediatric Patients.AIDS research and human retroviruses · 2015Article
- Significant reductions in Gag-protease-mediated HIV-1 replication capacity during the course of the epidemic in Japan.Journal of virology · 2013Article
- Gag-Pol processing during HIV-1 virion maturation: a systems biology approach.PLoS computational biology · 2013Article
- Role of the SP2 domain and its proteolytic cleavage in HIV-1 structural maturation and infectivity.Journal of virology · 2012Article
- Human Immunodeficiency Virus Gag and protease: partners in resistance.Retrovirology · 2012Review
- Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease.Antimicrobial agents and chemotherapy · 2012Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMutations in the substrate of HIV-1 protease, especially changes in the NC/p1 cleavage site, can directly contribute to protease inhibitor (PI) resistance and also compensate for defects in viral replicative capacity (RC) due to a drug resistant protease. These NC/p1 changes are known to enhance processing of the Gag protein. To investigate the capacity of HIV-1 to modulate Gag cleavage and its consequences for PI resistance and RC, we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2431V, HXB2436E+437T, HXB2437T and HXB2437V).
resultsHere, we demonstrate that single NC/p1 mutants, which displayed only a slight increase in PI resistance did not show an obvious change in RC. In contrast, the double NC/p1 mutant, which displayed a clear increase in processing efficiency and PI resistance, demonstrated a clear reduction in RC. Cleavage analysis showed that a tridecameric NC/p1 peptide representing the double NC/p1 mutant was cleaved in two specific ways instead of one.The observed decrease in RC for the double NC/p1 mutant (HXB2436E+437T) could (partially) be restored by either reversion of the 436E change or by acquisition of additional changes in the NC/p1 cleavage site at codon 435 or 438 as was revealed during in vitro evolution experiments. These changes not only restored RC but also reduced PI resistance levels. Furthermore these changes normalized Gag processing efficiency and obstructed the novel secondary cleavage site observed for the double NC/p1 mutant.
conclusionsThe results of this study clearly demonstrate that HIV-1 can modulate Gag processing and thereby PI resistance. Distinct increases in Gag cleavage and PI resistance result in a reduced RC that can only be restored by amino acid changes in NC/p1 which reduce Gag processing to an optimal rate.
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