The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients1

ABSTRACT In order to track the evolution of primary protease inhibitor (PI) resistance mutations in human immunodeficiency virus type 1 (HIV-1) isolates, baseline and follow-up protease sequences were obtained from patients undergoing salvage PI therapy who presented initially with isolates containing a single primary PI resistance mutation. Among 78 patients meeting study selection criteria, baseline primary PI resistance mutations included L90M (42% of patients), V82A/F/T (27%), D30N (21%), G48V (6%), and I84V (4%). Despite the switching of treatment to a new PI, primary PI resistance mutations present at the baseline persisted in 66 of 78 (85%) patients. D30N persisted less frequently than L90M (50% versus 100%, respectively; P < 0.001) and V82A/F/T (50% versus 81%, respectively; P = 0.05). HIV-1 isolates from 38 (49%) patients failing PI salvage therapy developed new primary PI resistance mutations including L90M, I84V, V82A, and G48V. Common combinations of primary and secondary PI resistance mutations after salvage therapy included mutations at amino acid positions 10, 82, and 46 and/or 54 in 16 patients; 10, 90, and 71 and/or 73 in 14 patients; 10, 73, 84, 90, and 46 and/or 54 in 5 patients; 10, 48, and 82 in 5 patients; and 30, 88 and 90 in 5 patients. In summary, during salvage PI therapy, most HIV-1 isolates with a single primary PI resistance mutation maintained their original mutations, and 49% developed additional primary PI resistance mutations. The persistence of L90M, V82A/F/T, G48V, and I84V during salvage therapy suggests that these mutations play a role in clinical resistance to multiple PIs.

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Protease Inhibitor Resistance Analysis in the MONARK Trial Comparing First-Line Lopinavir-Ritonavir Monotherapy to Lopinavir-Ritonavir plus Zidovudine and Lamivudine Triple Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01643-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2934-2939 ◽

Cited By ~ 43

Author(s):

Constance Delaugerre ◽

Philippe Flandre ◽

Marie Laure Chaix ◽

Jade Ghosn ◽

François Raffi ◽

...

Keyword(s):

Protease Inhibitor ◽

Triple Therapy ◽

Virological Failure ◽

Therapy Group ◽

Resistance Mutation ◽

Resistance Testing ◽

Initial Screening ◽

Resistance Mutations ◽

Cd4 Cell Count ◽

Hiv 1

ABSTRACT The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society—USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.

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Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0000000000000568 ◽

2015 ◽

Vol 69 (2) ◽

pp. 138-144 ◽

Cited By ~ 7

Author(s):

Camille Marie Lange ◽

Stéphane Hué ◽

Avy Violari ◽

Mark Cotton ◽

Diana Gibb ◽

...

Keyword(s):

Drug Resistance ◽

Protease Inhibitor ◽

Genome Analysis ◽

Resistance Mutations ◽

First Line ◽

Drug Resistance Mutations ◽

First Line Therapy ◽

Line Therapy ◽

Single Genome ◽

Hiv 1

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05549-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 623-633 ◽

Cited By ~ 21

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.

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Long-term follow-up of 11 protease inhibitor (PI)-naïve and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene

HIV Medicine ◽

10.1111/j.1468-1293.2010.00862.x ◽

2010 ◽

Vol 12 (3) ◽

pp. 138-144 ◽

Cited By ~ 6

Author(s):

C Amiel ◽

C Charpentier ◽

N Désiré ◽

P Bonnard ◽

M-G Lebrette ◽

...

Keyword(s):

Protease Inhibitor ◽

Protease Gene ◽

Long Term Follow Up ◽

Hiv 1

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Salvage therapy with abacavir plus a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor in heavily pre-treated HIV-1 infected patients

AIDS ◽

10.1097/00002030-200005050-00004 ◽

2000 ◽

Vol 14 (7) ◽

pp. 791-799 ◽

Cited By ~ 26

Author(s):

Nina Khanna ◽

Thomas Klimkait ◽

Veronique Schiffer ◽

Jose Irigoyen ◽

Amalio Telenti ◽

...

Keyword(s):

Protease Inhibitor ◽

Reverse Transcriptase ◽

Salvage Therapy ◽

Nucleoside Reverse Transcriptase Inhibitor ◽

Transcriptase Inhibitor ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1

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Salvage therapy with abacavir plus efavirenz or nevirapine in HIV-1-infected persons with previous nucleoside analogue and protease inhibitor use

AIDS ◽

10.1097/00002030-200007070-00020 ◽

2000 ◽

Vol 14 (10) ◽

pp. 1453-1454 ◽

Cited By ~ 17

Author(s):

Graeme J. Moyle ◽

Ed Wilkins ◽

Clifford Leen ◽

Ann Cheesbrough ◽

Brian Reynolds ◽

...

Keyword(s):

Protease Inhibitor ◽

Nucleoside Analogue ◽

Salvage Therapy ◽

Hiv 1

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Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538)

AIDS ◽

10.1097/00002030-199610090-00010 ◽

1996 ◽

Vol 10 (9) ◽

pp. 995-999 ◽

Cited By ~ 71

Author(s):

Jean-Claude Schmit ◽

Lidia Ruiz ◽

Bonaventura Clotet ◽

Antoni Raventos ◽

Jordi Tor ◽

...

Keyword(s):

Protease Inhibitor ◽

Protease Gene ◽

Hiv 1

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

Journal of Virology ◽

10.1128/jvi.01640-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 768-779 ◽

Cited By ~ 15

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.

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