Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease.

ABSTRACT Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I+I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P = 0.014 and P = 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.

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Effect of linker insertion mutations in the human immunodeficiency virus type 1 gag gene on activation of viral protease expressed in bacteria.

Journal of Virology ◽

10.1128/jvi.67.6.3630-3634.1993 ◽

1993 ◽

Vol 67 (6) ◽

pp. 3630-3634 ◽

Cited By ~ 6

Author(s):

J Luban ◽

C Lee ◽

S P Goff

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Viral Protease ◽

Immunodeficiency Virus ◽

Insertion Mutations

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A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

Journal of Virology ◽

10.1128/jvi.77.10.5685-5693.2003 ◽

2003 ◽

Vol 77 (10) ◽

pp. 5685-5693 ◽

Cited By ~ 58

Author(s):

J. Gerardo García-Lerma ◽

Hamish MacInnes ◽

Diane Bennett ◽

Patrick Reid ◽

Soumya Nidtha ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Phenotypic Expression ◽

Cross Resistance ◽

Phenotypic Characterization ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Selection Of

ABSTRACT Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons. Resistance to d4T is not fully understood, although the selection of AZT resistance mutations in patients treated with d4T suggests that both drugs have similar pathways of resistance. Through the analysis of genotypic changes in nine recombinant viruses cultured with d4T, we identified a new pathway for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged viruses were derived from treatment-naïve persons or HIV-1HXB2 and had wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected in seven viruses and was associated with a high level of enzymatic resistance to d4T-triphosphate (median, 16-fold; range, 5- to 48-fold). The role of K65R in d4T resistance was confirmed in site-directed mutants generated in three different RT backgrounds. Phenotypic assays based on recombinant single-cycle replication or a whole-virus multiple replication cycle were unable to detect d4T resistance in d4T-selected mutants with K65R but detected cross-resistance to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D mutations at baseline acquired the 215Y mutation alone or in association with K65R. Mutants having K65R and T215Y replicated less efficiently than viruses that had T215Y only, suggesting that selection of T215Y in patients treated with d4T may be favored. Our results demonstrate that K65R plays a role in d4T resistance and indicate that resistance pathways for d4T and AZT may not be identical. Biochemical analysis and improved replication assays are both required for a full phenotypic characterization of resistance to d4T. These findings highlight the complexity of the genetic pathways of d4T resistance and its phenotypic expression.

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Human immunodeficiency virus type 1 Vif-derived peptides inhibit the viral protease and arrest virus production

Peptide Science — Present and Future ◽

10.1007/0-306-46864-6_145 ◽

2006 ◽

pp. 439-441

Author(s):

C. Gilon ◽

A. Friedler ◽

L. Baraz ◽

I. Blumenzweig ◽

O. Nussinuv ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Virus Production ◽

Viral Protease ◽

Immunodeficiency Virus

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Interaction of human immunodeficiency virus type 1 Vif with Gag and Gag–Pol precursors: co-encapsidation and interference with viral protease-mediated Gag processing

Journal of General Virology ◽

10.1099/0022-1317-82-11-2719 ◽

2001 ◽

Vol 82 (11) ◽

pp. 2719-2733 ◽

Cited By ~ 27

Author(s):

Martine Bardy ◽

Bernard Gay ◽

Stéphanie Pébernard ◽

Nathalie Chazal ◽

Marianne Courcoul ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Viral Protease ◽

Extracellular Virus ◽

Immunodeficiency Virus ◽

Pr Domain

Interactions of human immunodeficiency virus type 1 (HIV-1) Vif protein with various forms of Gag and Gag–Pol precursors expressed in insect cells were investigated in vivo and in vitro by co-encapsidation, co-precipitation and viral protease (PR)-mediated Gag processing assays. Addressing of Gag to the plasma membrane, its budding as extracellular virus-like particles (VLP) and the presence of the p6 domain were apparently not required for Vif encapsidation, as non-N-myristoylated Δp6-Gag and Vif proteins were co-encapsidated into intracellular VLP. Encapsidation of Vif occurred at significantly higher copy numbers in extracellular VLP formed from N-myristoylated, budding-competent Gag–Pol precursors harbouring an inactive PR domain or in chimaeric VLP composed of Gag and Gag–Pol precursors compared with the Vif content of Pr55Gag VLP. Vif encapsidation efficiency did not seem to correlate directly with VLP morphology, since these chimaeric VLP were comparable in size and shape to Pr55Gag VLP. Vif apparently inhibited PR-mediated Pr55Gag processing in vitro, with preferential protection of cleavage sites at the MA–CA and CA–NC junctions. Vif was resistant to PR action in vitro under conditions that allowed full Gag processing, and no direct interaction between Vif and PR was detected in vivo or in vitro. This suggested that inhibition by Vif of PR-mediated Gag processing resulted from interaction of Vif with the Gag substrate and not with the enzyme. Likewise, the higher efficiency of Vif encapsidation by Gag–Pol precursor compared with Pr55Gag was probably not mediated by direct binding of Vif to the Gag–Pol-embedded PR domain, but more likely resulted from a particular conformation of the Gag structural domains of the Gag–Pol precursor.

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Risk Factors for Selection of the L74I Reverse Transcriptase Mutation in Human Immunodeficiency Virus Type 1-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00092-06 ◽

2006 ◽

Vol 50 (7) ◽

pp. 2553-2556 ◽

Cited By ~ 5

Author(s):

Marc Wirden ◽

Bénédicte Roquebert ◽

Anne Derache ◽

Anne Simon ◽

Claudine Duvivier ◽

...

Keyword(s):

Risk Factors ◽

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Thymidine Analog ◽

Immunodeficiency Virus ◽

Selection Of

ABSTRACT We analyzed 3,475 human immunodeficiency virus sequences and 241 therapeutic histories. The L74I mutation was carried by 7% of viruses. L74I was strongly associated with T215F, K70R, and V75M/S/T/A mutations and increased with the number of thymidine analog mutations. It seemed to be linked to the use of abacavir or efavirenz.

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Potential role of the viral protease in human immunodeficiency virus type 1 associated pathogenesis

Medical Hypotheses ◽

10.1016/0306-9877(92)90071-j ◽

1992 ◽

Vol 37 (3) ◽

pp. 137-150 ◽

Cited By ~ 9

Author(s):

R.L. Shoeman ◽

B. Höner ◽

E. Mothes ◽

P. Traub

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Potential Role ◽

Viral Protease ◽

Immunodeficiency Virus

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TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, ShowsIn Vitroan Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00748-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5723-5731 ◽

Cited By ~ 23

Author(s):

Inge Dierynck ◽

Herwig Van Marck ◽

Marcia Van Ginderen ◽

Tim H. M. Jonckers ◽

Madhavi N. L. Nalam ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitor ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Clinical Isolates ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Selection Of

ABSTRACTTMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC50], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC50, >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC50was ≤4 for 82% of isolates and ≤10 for 96% of isolates. The FC in TMC310911 EC50was ≤4 and ≤10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively.In vitroresistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC50= 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC50= 258). The activity against a comprehensive panel of PI-resistant mutants and the limitedin vitroselection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.

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