scholarly journals Virological and Pharmacological Parameters Predicting the Response to Lopinavir-Ritonavir in Heavily Protease Inhibitor-Experienced Patients

2005 ◽  
Vol 49 (5) ◽  
pp. 1720-1726 ◽  
Author(s):  
Anne-Geneviève Marcelin ◽  
Isabelle Cohen-Codar ◽  
Martin S. King ◽  
Philippe Colson ◽  
Emmanuel Guillevic ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Drug Exposure ◽  
Virologic Response ◽  
Therapeutic Drug ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
Hiv Rna ◽  
Inhibitor Resistance ◽  
Hiv 1

ABSTRACT The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of −1.50 log10 copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C min concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.

scholarly journals Interplay between Single Resistance-Associated Mutations in the HIV-1 Protease and Viral Infectivity, Protease Activity, and Inhibitor Sensitivity

2011 ◽  
Vol 56 (2) ◽  
pp. 623-633 ◽  
Author(s):  
Gavin J. Henderson ◽  
Sook-Kyung Lee ◽  
David M. Irlbeck ◽  
Janera Harris ◽  
Melissa Kline ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Protease Activity ◽  
Leukemia Virus ◽  
Fold Increase ◽  
Pleiotropic Effect ◽  
Viral Fitness ◽  
Resistance Mutations ◽  
Primary Resistance ◽  
Hiv 1

ABSTRACTResistance-associated mutations in the HIV-1 protease modify viral fitness through changes in the catalytic activity and altered binding affinity for substrates and inhibitors. In this report, we examine the effects of 31 mutations at 26 amino acid positions in protease to determine their impact on infectivity and protease inhibitor sensitivity. We found that primary resistance mutations individually decrease fitness and generally increase sensitivity to protease inhibitors, indicating that reduced virion-associated protease activity reduces virion infectivity and the reduced level of per virion protease activity is then more easily titrated by a protease inhibitor. Conversely, mutations at more variable positions (compensatory mutations) confer low-level decreases in sensitivity to all protease inhibitors with little effect on infectivity. We found significant differences in the observed effect on infectivity with a pseudotype virus assay that requires the protease to cleave the cytoplasmic tail of the amphotropic murine leukemia virus (MuLV) Env protein. Additionally, we were able to mimic the fitness loss associated with resistance mutations by directly reducing the level of virion-associated protease activity. Virions containing 50% of a D25A mutant protease were 3- to 5-fold more sensitive to protease inhibitors. This level of reduction in protease activity also resulted in a 2-fold increase in sensitivity to nonnucleoside inhibitors of reverse transcriptase and a similar increase in sensitivity to zidovudine (AZT), indicating a pleiotropic effect associated with reduced protease activity. These results highlight the interplay between enzyme activity, viral fitness, and inhibitor mechanism and sensitivity in the closed system of the viral replication complex.

scholarly journals Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

2015 ◽  
Vol 90 (2) ◽  
pp. 768-779 ◽  
Author(s):  
Angelica N. Martins ◽  
Abdul A. Waheed ◽  
Sherimay D. Ablan ◽  
Wei Huang ◽  
Alicia Newton ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Biochemical Analysis ◽  
Replication Capacity ◽  
Resistance Mutations ◽  
Cellular Machinery ◽  
Ptap Motif ◽  
Hiv 1

ABSTRACTHIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr-Ala-Pro (PTAP), located in the p6 region of Gag (p6Gag), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6Gagsignificantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6Gagconfers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy.IMPORTANCEResistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala-Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients.

Diverse pattern of protease inhibitor resistance mutations in HIV-1 infected patients failing nelfinavir

2005 ◽  
Vol 76 (4) ◽  
pp. 447-451 ◽  
Author(s):  
Veronica Svedhem ◽  
A. Lindkvist ◽  
T. Bergroth ◽  
Lidman Knut ◽  
A. Sönnerborg
Keyword(s):  
Protease Inhibitor ◽  
Resistance Mutations ◽  
Protease Inhibitor Resistance ◽  
Inhibitor Resistance ◽  
Hiv 1 ◽  
Diverse Pattern

Influence of Major HIV-1 Protease Inhibitor Resistance Mutations on CTL Recognition

2011 ◽  
Vol 56 (2) ◽  
pp. 109-117 ◽  
Author(s):  
Sandra M Mueller ◽  
Bernd M Spriewald ◽  
Silke Bergmann ◽  
Kathrin Eismann ◽  
Melanie Leykauf ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Resistance Mutations ◽  
Protease Inhibitor Resistance ◽  
Inhibitor Resistance ◽  
Hiv 1

scholarly journals HIV-1 Gag Non-Cleavage Site PI Resistance Mutations Stabilize Protease/Gag Substrate Complexes in Silico via a Substrate-Clamp

BioChem ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 190-209
Author(s):  
Gary S. Laco
Keyword(s):  
Protease Inhibitor ◽  
Active Site ◽  
In Silico ◽  
Cleavage Site ◽  
Cleavage Sites ◽  
Resistance Mutations ◽  
Cleavage Rate ◽  
Protease Inhibitor Resistance ◽  
Inhibitor Resistance ◽  
Hiv 1

HIV-1 protease active site inhibitors are a key part of antiretroviral therapy, though resistance can evolve rendering therapy ineffective. Protease inhibitor resistance typically starts with primary mutations around the active site, which reduces inhibitor binding, protease affinity for substrate cleavage site residues P4-P4′, and viral replication. This is often followed by secondary mutations in the protease substrate-grooves which restore viral replication by increasing protease affinity for cleavage site residues P12-P5/P5′-P12′, while maintaining resistance. However, mutations in Gag alone can also result in resistance. The Gag resistance mutations can occur in cleavage sites (P12-P12′) to increase PR binding, as well as at non-cleavage sites. Here we show in silico that Gag non-cleavage site protease inhibitor resistance mutations can stabilize protease binding to Gag cleavage sites which contain structured subdomains on both sides: SP1/NC, SP2/p6, and MA/CA. The Gag non-cleavage site resistance mutations coordinated a network of H-bond interactions between the adjacent structured subdomains of the Gag substrates to form a substrate-clamp around the protease bound to cleavage site residues P12-P12′. The substrate-clamp likely slows protease disassociation from the substrate, restoring the cleavage rate in the presence of the inhibitor. Native Gag substrates can also form somewhat weaker substrate-clamps. This explains the 350-fold slower cleavage rate for the Gag CA/SP1 cleavage site in that the CA-SP1 substrate lacks structured subdomains on both sides of the cleavage site, and so cannot form a substrate-clamp around the PR.

Low Trough Plasma Concentrations of Nevirapine Associated with Virologic Rebounds in HIV-Infected Patients Who Switched from Protease Inhibitors

2005 ◽  
Vol 39 (4) ◽  
pp. 603-609 ◽  
Author(s):  
Michel Duong ◽  
Marielle Buisson ◽  
Gilles Peytavin ◽  
Evelyne Kohli ◽  
Lionel Piroth ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Virologic Failure ◽  
Plasma Concentrations ◽  
Transcriptase Inhibitor ◽  
Virologic Response ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
The Mean ◽  
Reverse Transcriptase Inhibitor

BACKGROUND: The substitution of a nonnucleoside reverse-transcriptase inhibitor (NNRTI) for protease inhibitors (PIs) has demonstrated its suitability to maintain virologic response. However, the switch from PIs to an NNRTI could fail for a number of reasons, including NNRTI-associated toxicity and emergence of NNRTI-resistant variants. OBJECTIVE: To describe the virologic failures among 74 HIV-infected patients who switched from PIs to nevirapine. METHODS: Virologic failure was defined as any rebound of the plasma HIV-RNA (pVL) levels >1000 copies/mL on one occasion or 2 consecutive intermittent viremia episodes defined as increases of the pVL >20 copies/mL but <1000 copies/mL. Virologic failures were investigated retrospectively by determining nevirapine trough concentrations and performing genotypic resistance analysis. RESULTS: The mean nevirapine concentration was significantly lower in patients with virologic failure in comparison with patients with virologic response (2572 ± 1642 vs 4550 ± 2084 ng/mL, respectively; p = 0.003). In multivariate analysis, the mean duration of undetectable pVL before the switch and the mean plasma concentration of nevirapine were significantly associated with virologic success with relative rates of 1.39 (95% CI 1.10 to 1.76, p = 0.006) and 2.7 (95% CI 1.37 to 5.41, p = 0.01), respectively. In patients with pVL >1000 copies/mL, nevirapine mutations and nucleoside reverse-transcriptase inhibitor mutations were found in 80% of the cases. CONCLUSIONS: The risk of virologic failure after the switch from PI to nevirapine is higher in cases of inadequate nevirapine plasma concentrations. Our data support prospective monitoring of nevirapine plasma concentrations to detect low concentrations prior to the emergence of resistance mutations.

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