Baseline HIV drug resistance profile predicts response to ritonavir-saquinavir protease inhibitor therapy in a community setting

Harrigan, P. Richard; Hertogs, Kurt; Verbiest, W; Pauwels, Rudi; Larder, Brendan A.; Kemp, Sharon D.; Bloor, Stuart; Yip, Benita; Hogg, Robert S.; Alexander, Christopher; Montaner, Julio

doi:10.1097/00002030-199910010-00008

Cited by 112 publications

(78 citation statements)

References 14 publications

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“…Third, the signed-sum method used in the multivariate analysis of the genotypic patterns helped to simplify complex data and avoid the potential problem of colinearity between mutation predictors. Finally, recent retrospective studies support our findings, although not all of these studies have shown that the predictive capacity of resistance testing is independent of standard clinical predictors (37,(53)(54)(55)(56).…”

Section: Discussionsupporting

confidence: 83%

“…Mutations at these codons are known to be associated with resistance to one of the nucleoside reverse transcriptase inhibitors (25,45). In the protease gene, mutations at codons 30,46,48,54,82,84, and 90 were evaluated as potential predictors. We chose these "major" mutations a priori because they are associated with in vitro resistance to a protease inhibitor or occur commonly in patients in whom therapy with currently licensed protease inhibitors is failing.…”

Section: Hiv Genotypingmentioning

confidence: 99%

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HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

et al. 1999

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Section: Discussionsupporting

confidence: 83%

Section: Hiv Genotypingmentioning

confidence: 99%

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

et al. 1999

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“…due position 93 are associated with virological failure to saquinavir in combination with ritonavir [42,49]. Although the other polymorphisms in the C-SA protease have not been associated with virological failure in clinical studies, they may still contribute to the observed reduced drug susceptibility of the C-SA protease.…”

Section: Effect Of Secondary Resistance Mutations On Flap Movementmentioning

confidence: 97%

“…The M36I mutation is the only polymorphic mutation in the C-SA protease that is associated with drug resistance to most of the FDAapproved PIs in combination with ritonavir [41]. This mutation is associated with virological failure or a reduced virological response to atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir and tipranavir in combination with ritonavir [42][43][44][45][46][47][48][49]. Mutations at residue position 89 are associated with virological failure to darunavir and tipranavir in combination with ritonavir [44,50], and mutations at resi- In the subtype B protease (A) (PDB ID: 2PC0 [13]), M36 appears to provide anchorage for E35, and stabilizes the salt bridge between E35 and R57.…”

Section: Effect Of Secondary Resistance Mutations On Flap Movementmentioning

confidence: 99%

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

et al. 2014

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Since its identification, HIV has continued to have a detrimental impact on the lives of millions of people throughout the world. The protease of HIV is a major target in antiviral treatment. The South African HIV–1 subtype C (C–SA) protease displays weaker binding affinity for some clinically approved protease inhibitors in comparison with the HIV–1 subtype B protease. The heavy HIV burden in sub‐Saharan Africa, where subtype C HIV–1 predominates, makes this disparity a topic of great interest. In light of this, the enzyme activity and affinity of protease inhibitors for the subtype B and C–SA proteases were determined. The relative vitality, indicating the selective advantage of polymorphisms, of the C–SA protease relative to the subtype B protease in the presence of ritonavir and darunavir was four‐ and tenfold greater, respectively. Dynamic differences that contribute to the reduced drug susceptibility of the C–SA protease were investigated by performing hydrogen–deuterium exchange/mass spectrometry (HDX/MS) on unbound subtype B and C–SA proteases. The reduced propensity to form the E35–R57 salt bridge, and alterations in the hydrophobic core of the C–SA protease, are proposed to affect the anchoring of the flexible flaps, resulting in an increased proportion of the fully open flap conformation. HDX/MS data suggested that the N–terminus of both proteases is less stable than the C–terminus of the proteases, thus explaining the increased efficacy of dimerization inhibitors targeted toward the C–terminus of HIV proteases. As far as we are aware, this is the first report on assessment of HIV protease dynamics using HDX/MS.

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“…In addition, the emergence of HIV strains resistant to HAART has posed serious concerns for the viability of future treatments [164]. Most individuals discontinuing suppressive therapy have a rapid rebound in plasma viremia [165][166][167][168][169]. One explanation for this observation is the persistence of the virus in biological reservoirs.…”

Section: Hiv-1 Infectivity In Macrophagesmentioning

confidence: 99%

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Acevedo¹,

Ambrose²,

Flaherty³

et al. 2012

curr drug metab

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Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

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Baseline HIV drug resistance profile predicts response to ritonavir-saquinavir protease inhibitor therapy in a community setting

Abstract: Baseline resistance to ritonavir or saquinavir or both was associated with a poor antiviral response. Our data suggest that the measurement of drug resistance may assist in optimizing antiretroviral therapy in the clinic.

Cited by 112 publications

References 14 publications

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

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