Slow-, Tight-Binding HIV-1 Reverse Transcriptase Non-Nucleoside Inhibitors Highly Active against Drug-Resistant Mutants

ChemMedChem ◽  
2007 ◽  
Vol 2 (4) ◽  
pp. 445-448 ◽  
Author(s):  
Reynel Cancio ◽  
Antonello Mai ◽  
Dante Rotili ◽  
Marino Artico ◽  
Gianluca Sbardella ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Tight Binding ◽  
Drug Resistant ◽  
Highly Active ◽  
Resistant Mutants ◽  
Nucleoside Inhibitors ◽  
Hiv 1

Substrate-Induced Stable Enzyme-Inhibitor Complex Formation Allows Tight Binding of Novel 2-Aminopyrimidin-4(3H)-ones to Drug-Resistant HIV-1 Reverse Transcriptase Mutants

ChemMedChem ◽  
2008 ◽  
Vol 3 (9) ◽  
pp. 1412-1418 ◽  
Author(s):  
Alberta Samuele ◽  
Marcella Facchini ◽  
Dante Rotili ◽  
Antonello Mai ◽  
Marino Artico ◽  
...  
Keyword(s):  
Complex Formation ◽  
Reverse Transcriptase ◽  
Enzyme Inhibitor ◽  
Tight Binding ◽  
Drug Resistant ◽  
Inhibitor Complex ◽  
Hiv 1

scholarly journals Impact of Clinical Reverse Transcriptase Sequences on the Replication Capacity of HIV-1 Drug-Resistant Mutants

Virology ◽  
2001 ◽  
Vol 285 (2) ◽  
pp. 193-203 ◽  
Author(s):  
Carrie Dykes ◽  
Kora Fox ◽  
Amanda Lloyd ◽  
Michael Chiulli ◽  
Eugene Morse ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Replication Capacity ◽  
Drug Resistant ◽  
Resistant Mutants ◽  
Hiv 1

scholarly journals Evidence that Low-Level Viremias during Effective Highly Active Antiretroviral Therapy Result from Two Processes: Expression of Archival Virus and Replication of Virus

2005 ◽  
Vol 79 (15) ◽  
pp. 9625-9634 ◽  
Author(s):  
Nicole H. Tobin ◽  
Gerald H. Learn ◽  
Sarah E. Holte ◽  
Yang Wang ◽  
Ann J. Melvin ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Drug Resistant ◽  
Plasma Virus ◽  
Highly Active ◽  
Infected Cells ◽  
Resistant Mutants ◽  
Viral Sequences ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT Episodes of low-level viremia (LLV), with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels ranging from 50 to 400 copies (c)/ml, occur commonly during highly active antiretroviral therapy (HAART). LLV has been associated with virologic failure of HAART in some studies, while in others LLV did not appear to affect the clinical outcome. To understand the processes leading to LLV, genetic analyses were used to determine whether plasma virions emanated from archived or from newly evolved viral genomes. Episodes of LLV (plasma HIV-1 RNA, 50 to 379 [median, 77] c/ml) were detected in 21/37 (57%) HIV-1-infected children with median plasma HIV-1 RNA levels of <50 c/ml during 79 patient years of HAART. Viral sequences were derived by direct sequencing of PCR products from 21 plasma specimens diluted to end point. In phylogenetic analysis, LLV viral sequences grouped with virus from early in the course of infection in 8/11 subjects. Six specimens had multiple identical viral sequences, suggesting origin from clonally expanded infected cells. LLV plasma virus evolved over time, indicating viral replication, in 3/11 subjects. Two of these had frequent LLV, including the selection of drug-resistant mutants. In summary, plasma virus from episodes of LLV during effective HAART appeared to originate from two distinct processes, (i) clonal outgrowth from long-lived HIV-1-infected cells, presumably following activation and proliferation of these cells, and (ii) ongoing viral replication that included the selection of new drug-resistant mutants. These observations provide a plausible explanation for the divergent clinical outcomes previously associated with LLV.

scholarly journals Competitive Fitness of Nevirapine-Resistant Human Immunodeficiency Virus Type 1 Mutants

2004 ◽  
Vol 78 (2) ◽  
pp. 603-611 ◽  
Author(s):  
Jennifer A. Collins ◽  
M. Gregory Thompson ◽  
Elijah Paintsil ◽  
Melisa Ricketts ◽  
Joanna Gedzior ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Wild Type ◽  
Competitive Fitness ◽  
Immunodeficiency Virus ◽  
Resistant Mutants ◽  
Nevirapine Resistance ◽  
Hiv 1

ABSTRACT Determining the fitness of drug-resistant human immunodeficiency virus type 1 (HIV-1) strains is necessary for the development of population-based studies of resistance patterns. For this purpose, we have developed a reproducible, systematic assay to determine the competitive fitness of HIV-1 drug-resistant mutants. To demonstrate the applicability of this assay, we tested the fitness of the five most common nevirapine-resistant mutants (103N, 106A, 181C, 188C, and 190A), with mutations in HIV-1 reverse transcriptase (RT), singly and in combination (for a total of 31 variants) in a defined HIV-1 background. For these experiments, the 27 RT variants that produced viable virus were cocultured with wild-type virus without nevirapine. The ratios of the viral species were determined over time by utilization of a quantitative real-time RT-PCR-based assay. These experiments revealed that all of the viable variants were less fit than the wild type and demonstrated that the order of relative fitness of the single mutants tested was as follows: 103N > 181C > 190A > 188C > 106A. This order correlated with the commonality of these mutants as a result of nevirapine monotherapy. These investigations also revealed that, on average, the double mutants were less fit than the single mutants and the triple mutants were less fit than the double mutants. However, the fitness of the single and double mutants was often not predictive of the fitness of the derivative triple mutants, suggesting the presence of complex interactions between the closely aligned residues that confer nevirapine resistance. This complexity was also evident from the observation that all three of the replication-competent quadruple mutants were fitter than most of the triple mutants, and in some cases, even the double mutants. Our data suggest that, in many cases, viral fitness is the determining factor in the evolution of nevirapine-resistant mutants in vivo, that interactions between the residues that confer nevirapine resistance are complex, and that these interactions substantially affect reverse transcriptase structure and/or function.

scholarly journals Multiple Viral Genetic Analyses Detect Low-Level Human Immunodeficiency Virus Type 1 Replication during Effective Highly Active Antiretroviral Therapy

2003 ◽  
Vol 77 (10) ◽  
pp. 5721-5730 ◽  
Author(s):  
Lisa M. Frenkel ◽  
Yang Wang ◽  
Gerald H. Learn ◽  
Jennifer L. McKernan ◽  
Giovanina M. Ellis ◽  
...  
Keyword(s):  
Viral Replication ◽  
Highly Active Antiretroviral Therapy ◽  
Genetic Distances ◽  
Drug Resistant ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Resistant Mutants ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT To evaluate human immunodeficiency virus type 1 (HIV-1) replication and selection of drug-resistant viruses during seemingly effective highly active antiretroviral therapy (HAART), multiple HIV-1 env and pol sequences were analyzed and viral DNA levels were quantified from nucleoside analog-experienced children prior to and during a median of 5.1 (range, 1.8 to 6.4) years of HAART. Viral replication was detected at different rates, with apparently increasing sensitivity: 1 of 10 by phylogenetic analysis; 2 of 10 by viral evolution with increasing genetic distances from the most recent common ancestor (MRCA) of infection; 3 of 10 by selection of drug-resistant mutants; and 6 of 10 by maintenance of genetic distances from the MRCA. When four- or five-drug antiretroviral regimens were given to these children, persistent plasma viral rebound did not occur despite the accumulation of highly drug-resistant genotypes. Among the four children without genetic evidence of viral replication, a statistically significant decrease in the genetic distance to the MRCA was detected in three, indicating the persistence of a greater number of early compared to recent viruses, and their HIV-1 DNA decreased by ≥0.9 log10, resulting in lower absolute DNA levels (P = 0.007). This study demonstrates the variable rates of viral replication when HAART has suppressed plasma HIV-1 RNA for years to a median of <50 copies/ml and that combinations of four or five antiretroviral drugs suppress viral replication even after short-term virologic failure of three-drug HAART and despite ongoing accumulation of drug-resistant mutants. Furthermore, the decrease of cellular HIV-1 DNA to low absolute levels in those without genetic evidence of viral replication suggests that monitoring viral DNA during HAART may gauge low-level replication.

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