Co-evolution of nelfinavir-resistant HIV-1 protease and the p1–p6 substrate

Kolli, Madhavi; Lastère, Stéphane; Schiffer, Celia A.

doi:10.1016/j.virol.2005.11.049

Cited by 51 publications

(54 citation statements)

References 13 publications

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“…This effect is even more pronounced in subtype AE, where N88S pulls D30 out of the active site (21). We also showed that D30 not only is key for inhibitor binding but also is essential for recognition of the p1-p6 cleavage site (8,15,22). Consequently, the D30N mutation, which lowers affinity for NFV (23), also likely compromises p1-p6 recognition, leading to coevolution of this cleavage site (15).…”

Section: H Uman Immunodeficiency Virus Type 1 (Hiv-1) Protease (Pr)mentioning

confidence: 69%

“…While some of these mutations may compensate for loss of viral fitness and improve efficiency of Gag processing by the resistant PR (11, 13), we previously found that they may also directly modulate drug resistance (14). Frequently, these mutations arise within the Gag cleavage sites, particularly the NC-p1 and p1-p6 sites (15)(16)(17)(18). Cleavage site mutations have been specifically associated with several major protease resistance mutations (14,16,17), suggesting that as the virus evolves resistance to protease inhibitors with prolonged protease inhibitor therapy, evolution of cleavage sites could be a fairly frequent mechanism for maintaining viral fitness.…”

Section: H Uman Immunodeficiency Virus Type 1 (Hiv-1) Protease (Pr)mentioning

confidence: 99%

“…Previously, we reported that the p1-p6 cleavage site coevolves with the D30N/N88D PR mutations (14,15) in HIV-1 subtype B. The D30N mutation at the PR active site arises specifically in response to nelfinavir (NFV) inhibition, both in viral cultures and in patients being treated with NFV, and is often accompanied by the N88D secondary mutation, causing severe resistance to NFV (19).…”

Section: H Uman Immunodeficiency Virus Type 1 (Hiv-1) Protease (Pr)mentioning

confidence: 99%

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HIV-1 Protease-Substrate Coevolution in Nelfinavir Resistance

Kolli

Özen

KurtYilmaz

et al. 2014

J Virol

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Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue 30's interaction with the substrate are compensated by the coevolving L449F and S451N cleavage site mutations. This interdependency in the PR-p1-p6 interactions enhances intermolecular contacts and reinforces the overall fit of the substrate within the substrate envelope, likely enabling coevolution to sustain substrate recognition and cleavage in the presence of PR resistance mutations. IMPORTANCEResistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. Mutations in HIV-1 protease selected under the pressure of protease inhibitors render the inhibitors less potent. Occasionally, Gag sequences also mutate and coevolve with protease, contributing to maintenance of viral fitness and to drug resistance. In this study, we investigated the structural basis of coevolution at the Gag p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations. Our structural analysis reveals the interdependency of protease-substrate interactions and how coevolution may restore substrate recognition and cleavage in the presence of protease drug resistance mutations.

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Section: H Uman Immunodeficiency Virus Type 1 (Hiv-1) Protease (Pr)mentioning

confidence: 69%

Section: H Uman Immunodeficiency Virus Type 1 (Hiv-1) Protease (Pr)mentioning

confidence: 99%

Section: H Uman Immunodeficiency Virus Type 1 (Hiv-1) Protease (Pr)mentioning

confidence: 99%

See 1 more Smart Citation

HIV-1 Protease-Substrate Coevolution in Nelfinavir Resistance

Kolli

Özen

KurtYilmaz

et al. 2014

J Virol

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“…Therefore, as is evident from our enzyme kinetics data, the D30N/N88D mutations in clade B will likely affect substrate binding and processing. Several studies have observed substrate coevolution in instances in which the protease mutates active-site residues in order to confer inhibitor resistance (22,23). However, since the AE-N88S protease variant has no active-site mutations, the enzyme retains the ability to effectively recognize substrates while conferring NFV resistance.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Clade-Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways

Bandaranayake

Kolli

King

et al. 2010

J Virol

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The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01_AE (AE) strain is seen principally in Southeast Asia. AE protease differs by ϳ10% in amino acid sequence from clade B protease and carries several naturally occurring polymorphisms that are associated with drug resistance in clade B. AE protease has been observed to develop resistance through a nonactive-site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active-site mutation D30N and the nonactive-site mutation N88D. Structural and biochemical studies were carried out with wild-type and NFV-resistant clade B and AE protease variants. The relationship between clade-specific sequence variations and pathways to inhibitor resistance was also assessed. AE protease has a lower catalytic turnover rate than clade B protease, and it also has weaker affinity for both NFV and darunavir (DRV). This weaker affinity may lead to the nonactive-site N88S variant in AE, which exhibits significantly decreased affinity for both NFV and DRV. The D30N/N88D mutations in clade B resulted in a significant loss of affinity for NFV and, to a lesser extent, for DRV. A comparison of crystal structures of AE protease shows significant structural rearrangement in the flap hinge region compared with those of clade B protease and suggests insights into the alternative pathways to NFV resistance. In combination, our studies show that sequence polymorphisms within clades can alter protease activity and inhibitor binding and are capable of altering the pathway to inhibitor resistance.

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“…Synthetic peptides, however, are a poor substitute for the Gag polyprotein in terms of long-range intermolecular interactions and conformational changes that can alter the accessibility of Gag cleavage junctions. Additionally both protease and Gag mutate and coevolve in response to protease inhibitors in current clinical use (10)(11)(12)(13)(14)(15)(16)(17). Primary mutations (i.e., mutations at the catalytic site of protease) and mutations within the Gag cleavage sites are readily amenable to investigation using peptide analogs.…”

mentioning

confidence: 99%

Transient HIV-1 Gag–protease interactions revealed by paramagnetic NMR suggest origins of compensatory drug resistance mutations

Deshmukh

Louis

Ghirlando

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cleavage of the group-specific antigen (Gag) polyprotein by HIV-1 protease represents the critical first step in the conversion of immature noninfectious viral particles to mature infectious virions. Selective pressure exerted by HIV-1 protease inhibitors, a mainstay of current anti–HIV-1 therapies, results in the accumulation of drug resistance mutations in both protease and Gag. Surprisingly, a large number of these mutations (known as secondary or compensatory mutations) occur outside the active site of protease or the cleavage sites of Gag (located within intrinsically disordered linkers connecting the globular domains of Gag to one another), suggesting that transient encounter complexes involving the globular domains of Gag may play a role in guiding and facilitating access of the protease to the Gag cleavage sites. Here, using large fragments of Gag, as well as catalytically inactive and active variants of protease, we probe the nature of such rare encounter complexes using intermolecular paramagnetic relaxation enhancement, a highly sensitive technique for detecting sparsely populated states. We show that Gag-protease encounter complexes are primarily mediated by interactions between protease and the globular domains of Gag and that the sites of transient interactions are correlated with surface exposed regions that exhibit a high propensity to mutate in the presence of HIV-1 protease inhibitors.

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Co-evolution of nelfinavir-resistant HIV-1 protease and the p1–p6 substrate

Cited by 51 publications

References 13 publications

HIV-1 Protease-Substrate Coevolution in Nelfinavir Resistance

HIV-1 Protease-Substrate Coevolution in Nelfinavir Resistance

The Effect of Clade-Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways

Transient HIV-1 Gag–protease interactions revealed by paramagnetic NMR suggest origins of compensatory drug resistance mutations

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