Neutralization of multiple laboratory and clinical isolates of human immunodeficiency virus type 1 (HIV-1) by antisera raised against gp120 from the MN isolate of HIV-1.

1992 ◽  
Vol 66 (7) ◽  
pp. 4464-4469 ◽  
Author(s):  
P W Berman ◽  
T J Matthews ◽  
L Riddle ◽  
M Champe ◽  
M R Hobbs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Clinical Isolates ◽  
Immunodeficiency Virus ◽  
Hiv 1

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

1997 ◽  
Vol 41 (5) ◽  
pp. 965-971 ◽  
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.

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 Neutralization of Infectivity of Diverse R5 Clinical Isolates of Human Immunodeficiency Virus Type 1 by gp120-Binding 2′F-RNA Aptamers

2003 ◽  
Vol 77 (23) ◽  
pp. 12692-12698 ◽  
Author(s):  
Makobetsa Khati ◽  
Michael Schüman ◽  
Jamal Ibrahim ◽  
Quentin Sattentau ◽  
Siamon Gordon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Antiretroviral Drugs ◽  
Clinical Isolates ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) has evolved a number of strategies to resist current antiretroviral drugs and the selection pressures of humoral and cellular adaptive immunity. For example, R5 strains, which use the CCR5 coreceptor for entry and are the dominant viral phenotype for HIV-1 transmission and AIDS pathogenesis, are relatively resistant to neutralization by antibodies, as are other clinical isolates. In order to overcome these adaptations, we raised nucleic acid aptamers to the SU glycoprotein (gp120) of the R5 strain, HIV-1Ba-L. These not only bound gp120 with high affinity but also neutralized HIV-1 infectivity in human peripheral blood mononuclear cells (PBMCs) by more than 1,000-fold. Furthermore, these aptamers were able to neutralize the infectivity of R5 clinical isolates of HIV-1 derived from group M (subtypes A, C, D, E, and F) and group O. One aptamer defined a site on gp120 that overlaps partially with the conserved, chemokine receptor-binding, CD4-induced epitope recognized by monoclonal antibody 17b. In contrast to the antibody, the site is accessible to aptamer in the absence of CD4 binding. Neutralizing aptamers such as this could be exploited to provide leads in developing alternative, efficacious anti-HIV-1 drugs and lead to a deeper understanding of the molecular interactions between the virus and its host cell.

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 Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent

2008 ◽  
Vol 52 (4) ◽  
pp. 1302-1317 ◽  
Author(s):  
Roger G. Ptak ◽  
Philippe A. Gallay ◽  
Dirk Jochmans ◽  
Andrew P. Halestrap ◽  
Urs T. Ruegg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcription ◽  
Clinical Isolates ◽  
Ppiase Activity ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Ca Protein

ABSTRACT Debio-025 is a synthetic cyclosporine with no immunosuppressive capacity but a high inhibitory potency against cyclophilin A (CypA)-associated cis-trans prolyl isomerase (PPIase) activity. A lack of immunosuppressive effects compared to that of cyclosporine was demonstrated both in vitro and in vivo. For three cyclosporines, the inhibitory potential against PPIase activity was quantitatively correlated with that against human immunodeficiency virus type 1 (HIV-1) replication. Debio-025 selectively inhibited the replication of HIV-1 in a CD4+ cell line and in peripheral blood mononuclear cells: potent activity was demonstrated against clinical isolates of various HIV-1 subtypes, including isolates with multidrug resistance to reverse transcriptase and protease inhibitors. Simian immunodeficiency virus and HIV-2 strains were generally resistant to inhibition by Debio-025; however, some notable exceptions of sensitive HIV-2 clinical isolates were detected. In two-drug combination studies, additive inhibitory effects were found between Debio-025 and 19 clinically used drugs of different classes. Clinical HIV-1 isolates that are naturally resistant to Debio-025 and that do not depend on CypA for infection were identified. Comparison of the amino acid sequences of the CypA binding domain of the capsid (CA) protein from Debio-025-sensitive and -resistant HIV-1 isolates indicated that resistance was mostly associated with an H87Q/P exchange. Mechanistically, cyclosporines competitively inhibit the binding of CypA to the HIV-1 CA protein, which is an essential interaction required for early steps in HIV-1 replication. By real-time PCR we demonstrated that early reverse transcription is reduced in the presence of Debio-025 and that late reverse transcription is almost completely blocked. Thus, Debio-025 seems to interfere with the function of CypA during the progression/completion of HIV-1 reverse transcription.

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 A novel virus capture assay reveals a differential acquisition of host HLA-DR by clinical isolates of human immunodeficiency virus type 1 expanded in primary human cells depending on the nature of producing cells and the donor source

2001 ◽  
Vol 82 (12) ◽  
pp. 2979-2987 ◽  
Author(s):  
Réjean Cantin ◽  
Geneviève Martin ◽  
Michel J. Tremblay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Host Cells ◽  
Clinical Isolates ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Donor Source

Previous findings indicated that HLA-DR is probably one of the most abundant cellular constituents incorporated within the human immunodeficiency virus type 1 (HIV-1) envelope. Given that the life-cycle of HIV-1 has been reported to be modulated by virion-bound host HLA-DR, an improved version of a virus capture technique was developed to assess the degree of HLA-DR incorporation in several clinical isolates of HIV-1 derived from primary human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDM). Analysis of virus stocks purified from PBMCs and MDM indicated that primary isolates of HIV-1 bearing distinct tropism (i.e. T-, macrophage-, and dual-tropic) all incorporate host cell membrane HLA-DR protein. The amount of incorporated HLA-DR varies among the primary HIV-1 isolates tested. Propagation of some clinical HIV-1 isolates in either autologous PBMCs or MDM resulted in differential incorporation of virion-bound cellular HLA-DR depending on the nature of the virus producer cells. Differences in the degree of HLA-DR incorporation were also noticed when macrophage-tropic isolates of HIV-1 were produced in MDM from different donors. Altogether these data show that the efficiency of HLA-DR incorporation into the envelope of primary isolates of HIV-1 is a multifactorial phenomenon since it is affected by the virus isolate itself, the nature of host cells (i.e. PBMCs or MDM) and the donor source.

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