Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents.

ABSTRACT To evaluate the cross-resistance profile of the human immunodeficiency virus type 1 protease inhibitor (PI) atazanavir (BMS-232632), a panel of 551 clinical isolates exhibiting a wide array of PI resistance profiles and a variety of genotypic patterns were assayed for susceptibility to atazanavir and six other PIs: amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. In general, reductions in atazanavir susceptibility in vitro required several amino acid changes and were relatively modest in degree, and susceptibility was retained among isolates resistant to one or two of the currently approved PIs. There was a clear trend toward loss of susceptibility to atazanavir, as isolates exhibited increasing levels of cross-resistance to multiple PIs. Atazanavir appeared to have a distinct resistance profile relative to each of the other six PIs tested based on susceptibility comparisons against this panel of resistant isolates. Analysis of the genotypic profiles of 943 PI-susceptible and -resistant clinical isolates identified a strong correlation between the presence of amino acid changes at specific residues (10I/V/F, 20R/M/I, 24I, 33I/F/V, 36I/L/V, 46I/L, 48V, 54V/L, 63P, 71V/T/I, 73C/S/T/A, 82A/F/S/T, 84V, and 90M) and decreased susceptibility to atazanavir. While no single substitution or combination of substitutions was predictive of atazanavir resistance (change, >3.0-fold), the presence of at least five of these substitutions correlated strongly with loss of atazanavir susceptibility. Mutations associated with reduced susceptibility to each of the other six PIs were also determined.

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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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Importance of method in the determination of syncytium-inducing phenotype of human immunodeficiency virus type 1 clinical isolates

Journal of Virological Methods ◽

10.1016/s0166-0934(96)02152-0 ◽

1997 ◽

Vol 64 (2) ◽

pp. 137-145 ◽

Cited By ~ 3

Author(s):

Corinne Liesnard ◽

Marie-Luce Delforge ◽

Michel Tchetcheroff ◽

Viviane De Maertelaer ◽

Claire-Michele Farber ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Clinical Isolates ◽

Immunodeficiency Virus

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Inhibition of Human Immunodeficiency Virus Type 1 Replication by Combination of Transcription Inhibitor K-12 and Other Antiretroviral Agents in Acutely and Chronically Infected Cells

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.3.492 ◽

1999 ◽

Vol 43 (3) ◽

pp. 492-497 ◽

Cited By ~ 14

Author(s):

Mika Okamoto ◽

Takashi Okamoto ◽

Masanori Baba

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Antiretroviral Agents ◽

Immunodeficiency Virus ◽

K 12 ◽

Hiv 1

ABSTRACT 8 - Difluoromethoxy - 1 - ethyl - 6 - fluoro - 1,4 - dihydro - 7 - [4 - (2 - methoxyphenyl) - 1 - piperazinyl] - 4 - oxoquinoline - 3 - carboxylic acid (K-12) has recently been identified as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In this study, we examined several combinations of K-12 and other antiretroviral agents for their inhibitory effects on HIV-1 replication in acutely and chronically infected cell cultures. Combinations of K-12 and a reverse transcriptase (RT) inhibitor, either zidovudine, lamivudine, or nevirapine, synergistically inhibited HIV-1 replication in acutely infected MT-4 cells. The combination of K-12 and the protease inhibitor nelfinavir (NFV) also synergistically inhibited HIV-1, whereas the synergism of this combination was weaker than that of the combinations with the RT inhibitors. K-12 did not enhance the cytotoxicities of RT and protease inhibitors. Synergism of the combinations was also observed in acutely infected peripheral blood mononuclear cells. The combination of K-12 and cepharanthine, a nuclear factor κB inhibitor, synergistically inhibited HIV-1 production in tumor necrosis factor alpha-stimulated U1 cells, a promonocytic cell line chronically infected with the virus. In contrast, additive inhibition was observed for the combination of K-12 and NFV. These results indicate that the combinations of K-12 and clinically available antiretroviral agents may have potential as chemotherapeutic modalities for the treatment of HIV-1 infection.

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Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.965 ◽

1997 ◽

Vol 41 (5) ◽

pp. 965-971 ◽

Cited By ~ 44

Author(s):

D Lamarre ◽

G Croteau ◽

E Wardrop ◽

L Bourgon ◽

D Thibeault ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Potent Inhibitor ◽

Clinical Isolates ◽

Target Cells ◽

Immunodeficiency Virus ◽

Hiv 1

Palinavir is a potent inhibitor of the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) proteases. Replication of laboratory strains (HIV-1, HIV-2, and simian immunodeficiency virus) and HIV-1 clinical isolates is inhibited by palinavir with 50% effective concentrations ranging from 0.5 to 30 nM. The average cytotoxic concentration of palinavir (35 microM) in the various target cells indicates a favorable therapeutic index. Potent antiviral activity is retained with increased doses of virus and with clinical isolates resistant to zidovudine (AZT), didanosine (ddI), or nevirapine. Combinations of palinavir with either AZT, ddI, or nevirapine demonstrate synergy or additivity in the inhibition of HIV-1 replication. Palinavir retains anti-HIV-1 activity when administered postinfection until times subsequent to the reverse transcription step. In chronically infected CR-10 cells, palinavir blocks Gag precursor polyprotein processing completely, reducing greater than 99% of infectious particle production. The results indicate that the antiviral activity of palinavir is specific to inhibition of the viral protease and occurs at a late stage in the replicative cycle of HIV-1. On the basis of the potent in vitro activity, low-level cytotoxicity, and other data, palinavir was selected for in-depth preclinical evaluation.

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Extent of Cross-Resistance between Agents Used To Treat Human Immunodeficiency Virus Type 1 Infection in Clinically Derived Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.3.909-912.2002 ◽

2002 ◽

Vol 46 (3) ◽

pp. 909-912 ◽

Cited By ~ 21

Author(s):

P. Richard Harrigan ◽

Brendan A. Larder

Keyword(s):

United States ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

The United States ◽

Cross Resistance ◽

Antiretroviral Agents ◽

Immunodeficiency Virus

ABSTRACT The phenomenon of cross-resistance to antiretroviral agents used to treat human immunodeficiency virus type 1 infection is well known but so far has been only qualitatively described. Here, we quantitate the degree of cross-resistance among all commonly prescribed antiretroviral agents in almost 5,000 clinically derived recombinant isolates collected in the United States since January 2000.

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