scholarly journals A Tight-Binding Mode of Inhibition Is Essential for Anti-Human Immunodeficiency Virus Type 1 Virucidal Activity of Nonnucleoside Reverse Transcriptase Inhibitors

2002 ◽  
Vol 46 (6) ◽  
pp. 1851-1856 ◽  
Author(s):  
Dimitrios Motakis ◽  
Michael A. Parniak
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Tight Binding ◽  
Binding Mode ◽  
Virucidal Activity ◽  
Reverse Transcriptase Inhibitors ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT It was previously found that certain nonnucleoside reverse transcriptase inhibitors (NNRTI) possess virucidal activity against human immunodeficiency virus type 1 (HIV-1), and it was suggested that the tight-binding mode of inhibition of reverse transcriptase might be important for this virucidal activity (Borkow et al., J. Virol. 71:3023-3030, 1997). To test this, we compared six different NNRTI, including three tight-binding NNRTI, namely UC781, efavirenz (EFV) (Sustiva), and 5-chloro-3-phenylsulfonylindole-2-carboxamide (CSIC), and three rapid-equilibrium NNRTI, delavirdine (DLV) (Rescriptor), nevirapine (NVP) (Viramune), and UC84, in a variety of virucidal tests. Incubation of isolated HIV-1 virions with UC781, EFV, or CSIC rapidly inactivated the virus, whereas DLV, NVP, and UC84 were ineffective in this respect. Exposure of H9+ cells chronically infected by HIV-1 to the tight-binding NNRTI abolished the infectivity of nascent virus subsequently produced by these cells following removal of extracellular drug, thereby preventing cell-to-cell virus transmission in the absence of exogenous drug. In contrast, cell-to-cell transmission of HIV was blocked by DLV, NVP, and UC84 only when the drug remained in the extracellular medium. Pretreatment of uninfected lymphocytoid cells with UC781, EFV, or CSIC, but not DLV, NVP, or UC84, protected these cells from subsequent HIV-1 infection in the absence of extracellular drug. The protective effect was dependent on both the dose of NNRTI and the viral load. The overall virucidal efficacy of the tight-binding NNRTI tested was CSIC > UC781 ≃ EFV. We conclude that the tight-binding mode of inhibition is an essential characteristic for virucidal NNRTI and that antiviral potency is an insufficient predictor for virucidal utility of NNRTI.

scholarly journals Mutants of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Resistant to Nonnucleoside Reverse Transcriptase Inhibitors Demonstrate Altered Rates of RNase H Cleavage That Correlate with HIV-1 Replication Fitness in Cell Culture

2000 ◽  
Vol 74 (18) ◽  
pp. 8390-8401 ◽  
Author(s):  
Richard H. Archer ◽  
Carrie Dykes ◽  
Peter Gerondelis ◽  
Amanda Lloyd ◽  
Philip Fay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Rnase H ◽  
Wild Type ◽  
Reverse Transcriptase Inhibitors ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Replication Fitness ◽  
Hiv 1

ABSTRACT Three mutants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (V106A, V179D, and Y181C), which occur in clinical isolates and confer resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs), were analyzed for RNA- and DNA-dependent DNA polymerization and RNase H cleavage. All mutants demonstrated processivities of polymerization that were indistinguishable from wild-type enzyme under conditions in which deoxynucleoside triphosphates were not limiting. The V106A reverse transcriptase demonstrated a three- to fourfold slowing of both DNA 3′-end-directed and RNA 5′-end-directed RNase H cleavage relative to both wild-type and V179D enzymes, similar to what was observed for P236L in a previously published study (P. Gerondelis et al., J. Virol. 73:5803–5813, 1999). In contrast, the Y181C reverse transcriptase demonstrated a selective acceleration of the secondary RNase H cleavage step during both modes of RNase H cleavage. The relative replication fitness of these mutants in H9 cells was assessed in parallel infections as well as in growth competition experiments. Of the NNRTI-resistant mutants, V179D was more fit than Y181C, and both of these mutants were more fit than V106A, which demonstrated the greatest reduction in RNase H cleavage. These findings, in combination with results from previous work, suggest that abnormalities in RNase H cleavage are a common characteristic of HIV-1 mutants resistant to NNRTIs and that combined reductions in the rates of DNA 3′-end- and RNA 5′-end-directed cleavages are associated with significant reductions in the replication fitness of HIV-1.

scholarly journals Inhibition of Human Immunodeficiency Virus by a New Class of Pyridine Oxide Derivatives

2003 ◽  
Vol 47 (9) ◽  
pp. 2951-2957 ◽  
Author(s):  
Miguel Stevens ◽  
Christophe Pannecouque ◽  
Erik De Clercq ◽  
Jan Balzarini
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Cell Cultures ◽  
New Class ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Amino Acid Mutations ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT A new class of pyridine oxide derivatives as inhibitors of human immunodeficiency virus type 1 (HIV-1) and/or HIV-2 replication in cell culture has been identified. The compounds, which specifically inhibit HIV-1, behave as typical nonnucleoside reverse transcriptase inhibitors (NNRTIs). The most active congener of this group, JPL-133 (UC-B3096), has a 50% effective concentration of 0.05 μg/ml for HIV-1(IIIB) with a selectivity index of approximately 760 in CEM cell cultures. However, the cytostatic activity of most pyridine oxide derivatives highly depended on the nature of the cell line. All compounds, including those pyridine oxide derivatives that inhibit both HIV-1 and HIV-2 replication, select for NNRTI-characteristic mutations in the HIV-1 reverse transcriptase of HIV-infected cell cultures (i.e., Lys103Asn, Val108Ile, Glu138Lys, Tyr181Cys and Tyr188His). These amino acid mutations emerged mostly through transition of guanine to adenine or adenine to guanine in the corresponding codons of the reverse transcriptase (RT) gene. The HIV-1-specific pyridine oxide derivatives lost their antiviral activity against HIV-1 strains containing these mutations in the RT. However, most compounds retained pronounced antiviral potency against virus strains that contained other NNRTI-characteristic RT mutations, such as Leu100Ile and Val179Asp. Furthermore, the complete lack of inhibitory activity of the pyridine oxide derivatives against recombinant HIV-2 RT and partial retention of anti-HIV-1 activity against HIV-1 strains that contain a variety of HIV-1-characteristic mutations suggest that the pyridine oxide derivatives must have a second target of antiviral action independent from HIV-1 RT.

scholarly journals Characterization and Structural Analysis of Novel Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involved in the Regulation of Resistance to Nonnucleoside Inhibitors

2007 ◽  
Vol 81 (20) ◽  
pp. 11507-11519 ◽  
Author(s):  
Francesca Ceccherini-Silberstein ◽  
Valentina Svicher ◽  
Tobias Sing ◽  
Anna Artese ◽  
Maria Mercedes Santoro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcriptase Inhibitors ◽  
Data Set ◽  
Nnrti Resistance ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Resistance to antivirals is a complex and dynamic phenomenon that involves more mutations than are currently known. Here, we characterize 10 additional mutations (L74V, K101Q, I135M/T, V179I, H221Y, K223E/Q, and L228H/R) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase which are involved in the regulation of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs). These mutations are strongly associated with NNRTI failure and strongly correlate with the classical NNRTI resistance mutations in a data set of 1,904 HIV-1 B-subtype pol sequences from 758 drug-naïve patients, 592 nucleoside reverse transcriptase inhibitor (NRTI)-treated but NNRTI-naïve patients, and 554 patients treated with both NRTIs and NNRTIs. In particular, L74V and H221Y, positively correlated with Y181C, were associated with an increase in Y181C-mediated resistance to nevirapine, while I135M/T mutations, positively correlated with K103N, were associated with an increase in K103N-mediated resistance to efavirenz. In addition, the presence of the I135T polymorphism in NNRTI-naïve patients significantly correlated with the appearance of K103N in cases of NNRTI failure, suggesting that I135T may represent a crucial determinant of NNRTI resistance evolution. Molecular dynamics simulations show that I135T can contribute to the stabilization of the K103N-induced closure of the NNRTI binding pocket by reducing the distance and increasing the number of hydrogen bonds between 103N and 188Y. H221Y also showed negative correlations with type 2 thymidine analogue mutations (TAM2s); its copresence with the TAM2s was associated with a higher level of zidovudine susceptibility. Our study reinforces the complexity of NNRTI resistance and the significant interplay between NRTI- and NNRTI-selected mutations. Mutations beyond those currently known to confer resistance should be considered for a better prediction of clinical response to reverse transcriptase inhibitors and for the development of more efficient new-generation NNRTIs.

scholarly journals Screening for antiretroviral drug resistance among treatment-naive human immunodeficiency virus type 1-infected individuals in Lebanon

2014 ◽  
Vol 8 (03) ◽  
pp. 339-348
Author(s):  
Jacques M Mokhbat ◽  
Nada M. Melhem ◽  
Ziad El-Khatib ◽  
Pierre Zalloua
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Viral Load ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Newly Diagnosed ◽  
Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

Introduction: Antiretroviral therapy (ART) has been successful at decreasing the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 drug resistance (HIVDR) among ART-naive patients has been documented to compromise the success of initial therapy. This study was conducted to determine the prevalence of HIVDR mutations among newly diagnosed drug-naive HIV-infected individuals in Lebanon. Methodology: Plasma samples from 37 newly diagnosed participants at various stages of HIV-1 infection were used to determine HIV-1 RNA viral load, isolate viral RNA, and amplify DNA by RT-PCR. Purified PCR products were used to perform genotypic resistance tests. Results: The prevalence of resistance mutations to nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRT), and protease inhibitors (PI) were 5.4%, 10.8%, and 8%, respectively. The major mutations detected in the study participants conferred resistance to NRTIs and NNRTIs recommended for HIV-1 treatment.  No significant relationship between HIV-1 viral load of participants and the mode of HIV-1 transmission or between the occurrence of HIVDR and the mode of transmission was found. Conclusions: To our knowledge, this is the first study on HIVDR mutations among newly diagnosed HIV-infected persons in Lebanon. The overall prevalence of HIVDR mutations detected in our study was 16%. Our results are important for evaluating the utility of the standard first-line regimens in use, determining the feasibility of HIVDR testing before the initiation of ART, as well as minimizing the emergence and transmission of HIVDR.

scholarly journals 1,1,3-Trioxo-2H,4H-Thieno[3,4-e][1,2,4]Thiadiazine (TTD) Derivatives: a New Class of Nonnucleoside Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitors with Anti-HIV-1 Activity

1998 ◽  
Vol 42 (3) ◽  
pp. 618-623 ◽  
Author(s):  
M. Witvrouw ◽  
M. E. Arranz ◽  
C. Pannecouque ◽  
R. Declercq ◽  
H. Jonckheere ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Host Cells ◽  
Cross Resistance ◽  
Reverse Transcriptase Inhibitors ◽  
Relationship Analysis ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 μM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3′-azido-3′-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.

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