scholarly journals Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action

2007 ◽  
Vol 59 (6) ◽  
pp. 1084-1095 ◽  
Author(s):  
A. Hombrouck ◽  
A. Hantson ◽  
B. van Remoortel ◽  
M. Michiels ◽  
J. Vercammen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mechanism Of Action ◽  
Immunodeficiency Virus ◽  
Selection Of

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

2003 ◽  
Vol 77 (10) ◽  
pp. 5685-5693 ◽  
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.

scholarly journals High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme

2005 ◽  
Vol 49 (11) ◽  
pp. 4546-4554 ◽  
Author(s):  
Reynel Cancio ◽  
Romano Silvestri ◽  
Rino Ragno ◽  
Marino Artico ◽  
Gabriella De Martino ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mechanism Of Action ◽  
Drug Resistant ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.

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

2006 ◽  
Vol 50 (7) ◽  
pp. 2553-2556 ◽  
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.

scholarly journals 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

2011 ◽  
Vol 55 (12) ◽  
pp. 5723-5731 ◽  
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.

scholarly journals Selection of Maternal Human Immunodeficiency Virus Type 1 Variants in Human Placenta

1999 ◽  
Vol 179 (1) ◽  
pp. 44-51 ◽  
Author(s):  
Elisabeth Menu ◽  
François‐Xavier M'bopi Kéou ◽  
Sylvie Lagaye ◽  
Serge Pissard ◽  
Philippe Mauclère ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Human Placenta ◽  
Immunodeficiency Virus ◽  
Selection Of

In vitro selection of human immunodeficiency virus type 1 resistant to 3′-azido-3′-deoxythymidine

1992 ◽  
Vol 18 (1) ◽  
pp. 39-52 ◽  
Author(s):  
Ferdinando Dianzani ◽  
Guido Antonelli ◽  
Ombretta Turriziani ◽  
Guanmu Dong ◽  
Maria R. Capobianchi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
In Vitro Selection ◽  
Immunodeficiency Virus ◽  
Selection Of
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