Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase.

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

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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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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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High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.37.10.2231 ◽

1993 ◽

Vol 37 (10) ◽

pp. 2231-2234 ◽

Cited By ~ 185

Author(s):

C A Boucher ◽

N Cammack ◽

P Schipper ◽

R Schuurman ◽

P Rouse ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Immunodeficiency Virus ◽

High Level ◽

Level Resistance

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High Prevalence of the K65R Mutation in Human Immunodeficiency Virus Type 1 Subtype C Isolates from Infected Patients in Botswana Treated with Didanosine-Based Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00714-06 ◽

2006 ◽

Vol 50 (12) ◽

pp. 4182-4185 ◽

Cited By ~ 70

Author(s):

Florence Doualla-Bell ◽

Ava Avalos ◽

Bluma Brenner ◽

Tendani Gaolathe ◽

Madisa Mine ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Subtype C ◽

K65r Mutation ◽

Immunodeficiency Virus ◽

High Prevalence

ABSTRACT We analyzed the reverse transcriptase genotypes of human immunodeficiency virus type 1 subtype C viruses isolated from 23 patients in Botswana treated with didanosine-based regimens. The K65R mutation was selected either alone or together with the Q151M, S68G, or F116Y substitution in viruses from seven such individuals. The results of in vitro passage experiments were consistent with an apparent increased propensity of subtype C viruses to develop the K65R substitution.

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