scholarly journals In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates.

1997 ◽  
Vol 41 (11) ◽  
pp. 2367-2373 ◽  
Author(s):  
K T Chong ◽  
P J Pagano
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Drug Combinations ◽  
Clinical Isolates ◽  
Immunodeficiency Virus ◽  
Hiv 1

PNU-140690 (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone) is a potent, nonpeptidic inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease currently under clinical evaluation. PNU-140690 and ritonavir were studied in two-drug combinations against the replication of HIV-1 clinical isolates in peripheral blood mononuclear cells. A ritonavir-sensitive (301-1x) and -resistant (301-6x) isolate pair derived from an individual before and after monotherapy with ritonavir were used. These isolates showed no significant difference in sensitivity to PNU-140690, but isolate 301-6x was more than 50-fold less sensitive to ritonavir than isolate 301-1x. Mathematical analysis showed that the combination of various concentrations of PNU-140690 with ritonavir yielded additive to moderately synergistic antiviral effects against the ritonavir-sensitive isolate and stronger synergy against the ritonavir-resistant isolate. The mechanism of synergy was not investigated, but the results suggested that both the virological and the observed in vitro pharmacological effects may have contributed to the observed synergy. Importantly, no significant antagonism was observed with the drug combinations studied. These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protease inhibitor such as ritonavir.

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 Estimate of the Frequency of Human Immunodeficiency Virus Type 1 Protease Inhibitor Resistance within Unselected Virus Populations In Vitro

1998 ◽  
Vol 42 (2) ◽  
pp. 478-480 ◽  
Author(s):  
Simon P. Tucker ◽  
Thomas R. Stiebel ◽  
Karen E. Potts ◽  
Mary L. Smidt ◽  
Martin L. Bryant
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Resistant Variant ◽  
Immunodeficiency Virus ◽  
Inhibitor Resistance ◽  
Hiv 1

ABSTRACT The frequency of drug-resistant human immunodeficiency virus type 1 (HIV-1) variants in virus populations not previously exposed to drug was determined in vitro by using HIV-1RF and the protease inhibitor SC-55389A. Two variants with single mutations responsible for drug resistance (V82A and N88S) were quantifiably isolated after only one round of replication, yielding a crude frequency estimate of at least 1 SC-55389A-resistant variant per 3.5 × 105wild-type infectious units.

scholarly journals Efficient Identification of Human Immunodeficiency Virus Type 1 Mutants Resistant to a Protease Inhibitor by Using a Random Mutant Library

2011 ◽  
Vol 55 (11) ◽  
pp. 5090-5098 ◽  
Author(s):  
Sanggu Kim ◽  
Yun-Cheol Kim ◽  
Hangfei Qi ◽  
Kunkai Su ◽  
Sherie L. Morrison ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTEmergence of drug-resistant mutant viruses during the course of antiretroviral therapy is a major hurdle that limits the success of chemotherapeutic treatment to suppress human immunodeficiency virus type 1 (HIV-1) replication and AIDS progression. Development of new drugs and careful patient management based on resistance genotyping data are important for enhancing therapeutic efficacy. However, identifying changes leading to drug resistance can take years of clinical studies, and conventionalin vitroassays are limited in generating reliable drug resistance data. Here we present an efficientin vitroscreening assay for selecting drug-resistant variants from a library of randomly mutated HIV-1 strains generated by transposon-directed base-exchange mutagenesis. As a test of principle, we screened a library of mutant HIV-1 strains containing random mutations in the protease gene by using a reporter T-cell line in the presence of the protease inhibitor (PI) nelfinavir (NFV). Analysis of replicating viruses from a single round of infection identified 50 amino acid substitutions at 35 HIV-1 protease residue positions. The selected mutant viruses showed specific resistance to NFV and included most of the known NFV resistance mutations. Therefore, the new assay is efficient for identifying changes leading to drug resistance. The data also provide insights into the molecular mechanisms underlying the development of drug resistance.

scholarly journals Characterization of a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, A-790742

2008 ◽  
Vol 52 (4) ◽  
pp. 1337-1344 ◽  
Author(s):  
Tatyana Dekhtyar ◽  
Teresa I. Ng ◽  
Liangjun Lu ◽  
Sherie Masse ◽  
David A. DeGoey ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
In Vitro Selection ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A-790742 is a potent human immunodeficiency virus type 1 (HIV-1) protease inhibitor, with 50% effective concentrations ranging from 2 to 7 nM against wild-type HIV-1. The activity of this compound is lowered by approximately sevenfold in the presence of 50% human serum. A-790742 maintained potent antiviral activity against lopinavir-resistant variants generated in vitro as well as against a panel of molecular clones containing proteases derived from HIV-1 patient isolates with multiple protease mutations. During in vitro selection, A-790742 selected two primary mutations (V82L and I84V) along with L23I, L33F, K45I, A71V/A, and V77I in the pNL4-3 background and two other mutations (A71V and V82G) accompanied by M46I and L63P in the HIV-1 RF background. HIV-1 pNL4-3 clones with a single V82L or I84V mutation were phenotypically resistant to A-790742 and ritonavir. Taking these results together, A-790742 displays a favorable anti-HIV-1 profile against both the wild type and a large number of mutants resistant to other protease inhibitors. The selection of the uncommon V82L and V82G mutations in protease by A-790742 suggests the potential for an advantageous resistance profile with this protease inhibitor.

scholarly journals Stronger Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against Clinical Isolates of Plasmodium vivax than against Those of P. falciparum

2008 ◽  
Vol 52 (7) ◽  
pp. 2435-2441 ◽  
Author(s):  
U. Lek-Uthai ◽  
R. Suwanarusk ◽  
R. Ruengweerayut ◽  
T. S. Skinner-Adams ◽  
F. Nosten ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Clinical Isolates ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Nm Range

ABSTRACT Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax (n = 30) and P. falciparum (n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum, compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.

scholarly journals TMC114, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor Active against Protease Inhibitor-Resistant Viruses, Including a Broad Range of Clinical Isolates

2005 ◽  
Vol 49 (6) ◽  
pp. 2314-2321 ◽  
Author(s):  
Sandra De Meyer ◽  
Hilde Azijn ◽  
Dominique Surleraux ◽  
Dirk Jochmans ◽  
Abdellah Tahri ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Effective Concentration ◽  
Clinical Isolates ◽  
Potential Candidate ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC50) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 μM (selectivity index, >20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC50s of <10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but <10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naïve and PI-experienced patients with HIV.

scholarly journals Synergistic Inhibition of Human Immunodeficiency Virus Type 1 Replication in Vitro by Two- and Three-Drug Combinations of Delavirdine, Lamivudine and Zidovudine

1997 ◽  
Vol 8 (4) ◽  
pp. 333-341 ◽  
Author(s):  
PJ Pagano ◽  
KT Chong
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Drug Combinations ◽  
Core Antigen ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
Hiv 1

Delavirdine (DLV), a non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, was evaluated in two- and three-drug combination regimens with lamivudine (3TC) and zidovudine (ZDV). The effect of continuous drug treatment on HIV-1JR-CSF replication in human peripheral blood mononuclear cells was measured by an ELISA for p24 core antigen. Drug synergy, estimated by the combination index method and the method of Pritchard & Shipman, was observed when DLV was combined with 3TC over a range of drug concentrations (DLV at 1, 3, 10, 30 and 100 nM; 3TC at 3, 10, 30, 100 and 300 nM). Two-drug combinations of ZDV and DLV at a 1: 3 ratio or ZDV and 3TC at a 1: 10 ratio were synergistic at greater than 75% inhibition levels. Three-drug combinations of ZDV, DLV and 3TC (ZDV at 0.3, 1, 3 and 10 nM; DLV at 1, 3, 10 and 30 nM; 3TC at 3, 10, 30 and 100 nM) at the ratio of 1: 3: 10 also yielded significant synergistic effects. None of the combinations studied showed significant additive or synergistic drug toxicity. These in vitro data suggest that DLV should be evaluated in two- and three-drug combinations with 3TC and ZDV in clinical trials.

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