699 results on '"Mark A. Wainberg"'
Search Results
102. Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance
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Mark A. Wainberg and Bluma G. Brenner
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0301 basic medicine ,Cancer Research ,Pyridones ,030106 microbiology ,Human immunodeficiency virus (HIV) ,Integrase inhibitor ,HIV Infections ,Drug resistance ,Microbial Sensitivity Tests ,medicine.disease_cause ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Virology ,Antiretroviral Therapy, Highly Active ,Drug Resistance, Viral ,Oxazines ,medicine ,Humans ,HIV Integrase Inhibitors ,biology ,Antiretroviral therapy ,Reverse transcriptase ,3. Good health ,Integrase ,Molecular Typing ,Infectious Diseases ,chemistry ,Dolutegravir ,Mutation ,biology.protein ,HIV-1 ,Heterocyclic Compounds, 3-Ring ,Hiv disease - Abstract
This manuscript reviews the reasons why Integrase inhibitors should now routinely constitute a part of first line antiretroviral therapy for the treatment of HIV disease. The use of these drugs that are generally well tolerated has resulted in far less drug resistance than was the case with most other categories of antiviral compounds. In addition, the integrase inhibitor family of drugs has been less prone to the problem of transmitted drug resistance which is due to a wide variety of substitutions in the HIV genome that can be sexually transmitted from one person to another. However, the use of integrase inhibitors in first line therapy may unfortunately not soon happen in developing country settings where non-nucleoside reverse transcriptase inhibitors continue to be a mainstay of initial therapy, primarily for reasons of cost. As long as this situation continues, problems of drug resistance and transmitted drug resistance will be common in such settings. Current evidence also suggests that the use of dolutegravir as a first line integrase inhibitor may limit development of drug resistance to an extent that exceeds the use of other members of this family of drugs. This may be due to particular patterns of resistance involving dolutegravir, whereby the mutations that are associated with resistance against this compound may actually diminish both HIV replication capacity as well as integrase enzymatic activity in a far-reaching and unique manner. This gives potential hope that the use of dolutegravir in first line therapy could actually form part of the long-sought goal of attainment of a functional cure for HIV disease.
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- 2016
103. The R263K resistance substitution decreases levels of integrated HIV DNA over time
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Mark A. Wainberg and Thibault Mesplède
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Infectious Diseases ,Resistance (ecology) ,Epidemiology ,Chemistry ,Virology ,Immunology ,Substitution (logic) ,Public Health, Environmental and Occupational Health ,Public aspects of medicine ,RA1-1270 ,Microbiology ,QR1-502 - Published
- 2016
104. Selection of the R263K and H51Y resistance substitutions for DTG causes diminished integration and explains the lack of clinically significant drug resistance to this compound
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Nathan Osman, Thibault Mesplède, Mark A. Wainberg, Katlin Anstett, Jiaming Liang, and Hanh T. Pham
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Genetics ,Resistance (ecology) ,Epidemiology ,Immunology ,Public Health, Environmental and Occupational Health ,Drug resistance ,Biology ,Microbiology ,QR1-502 ,Infectious Diseases ,Virology ,Public aspects of medicine ,RA1-1270 ,Selection (genetic algorithm) - Published
- 2016
105. CRISPR/Cas9: a double-edged sword when used to combat HIV infection
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Ben Berkhout, Chen Liang, Atze T. Das, Mark A. Wainberg, Amsterdam institute for Infection and Immunity, and Medical Microbiology and Infection Prevention
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0301 basic medicine ,Anti-HIV Agents ,HIV Infections ,Biology ,Models, Biological ,03 medical and health sciences ,Genome editing ,INDEL Mutation ,Proviruses ,Virology ,Drug Resistance, Viral ,Recombinase ,CRISPR ,Gene ,Genetics ,Transcription activator-like effector nuclease ,Cas9 ,Genetic Therapy ,Acquired immune system ,Zinc finger nuclease ,3. Good health ,Virus Latency ,030104 developmental biology ,Infectious Diseases ,HIV-1 ,Commentary ,CRISPR-Cas Systems - Abstract
The major barrier to eradication of HIV infection is the latent viral reservoir that persists despite long-term highly active antiretroviral therapy (HAART). The main reason for the existence of latently infected cells is that proviral DNA becomes integrated into the cellular genome. Theoretically, the elimination of proviral DNA from every infected cell should therefore be able to cure HIV infection. This concept has been tested in studies that employed designed recombinases [1], zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) bearing sequence-specific DNA-binding modules that recognize HIV DNA sequences [2]. In addition, the recent development of the bacterial adaptive immune system CRISPR/Cas9 for editing of genes in mammalian cells [3, 4] quickly led to the use of this new genome editing technology to try to inhibit and eliminate infection by different viruses, including HIV-1 [5].
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- 2016
106. ChemInform Abstract: Flueggether A and Virosinine A, anti-HIV Alkaloids from Flueggea virosa
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Jian-Min Yue, Kongkai Zhu, Hua Zhang, Mark A. Wainberg, Ying-Shan Han, and Cheng Luo
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Anti hiv activity ,chemistry.chemical_compound ,biology ,chemistry ,Anti hiv ,Stereochemistry ,Alkaloid ,Flueggea virosa ,Ether ,General Medicine ,biology.organism_classification ,Securinega ,Bridge (interpersonal) - Abstract
Flueggether A (I), the first example of Securinega alkaloid oligomers with an ether bridge, and virosinine A (II), possessing a novel heterocyclic backbone, exhibit weak in vitro anti-HIV activity.
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- 2016
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107. Might dolutegravir be part of a functional cure for HIV?
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Ying-Shan Han, Mark A. Wainberg, and Thibault Mesplède
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0301 basic medicine ,Pyridones ,Immunology ,Human immunodeficiency virus (HIV) ,HIV Infections ,Drug resistance ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Microbiology ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Drug Resistance, Viral ,Oxazines ,Genetics ,medicine ,Humans ,HIV Integrase Inhibitors ,Molecular Biology ,business.industry ,Elvitegravir ,General Medicine ,Raltegravir ,Virology ,Antiretroviral therapy ,Integrase strand transfer inhibitor ,030104 developmental biology ,chemistry ,Dolutegravir ,HIV-1 ,business ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.
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- 2016
108. ChemInform Abstract: New Securinega Alkaloids with anti-HIV Activity from Flueggea virosa
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Jian-Min Yue, Mark A. Wainberg, Chuan-Rui Zhang, Ying-Shan Han, and Hua Zhang
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Tryptamine ,Anti hiv activity ,biology ,Stereochemistry ,Dimer ,Alkaloid ,Chemical fractionation ,General Medicine ,biology.organism_classification ,Securinega ,chemistry.chemical_compound ,chemistry ,Flueggea virosa ,Piperidine - Abstract
Chemical fractionation of the ethanolic extract of Flueggea virosa yielded a group of Securinega alkaloids including flueggenines E (1) and F (2) as novel hybrid structures, flueggenines G–I (3–5) as new dimers and fluevirosines E–H (6–9) as new trimers, along with six known biosynthetically related compounds. The diverse structures of these isolates were characterized via comprehensive spectroscopic analyses and comparison with literature data. Compounds 1 and 2 are rare Securinega alkaloid hybrids incorporating tryptamine and piperidine residues, respectively, while 3 represents the first example bearing a securinine-type monomeric unit among Securinega alkaloid dimers. An in vitro anti-HIV screening of all available alkaloids revealed weak to moderate activities for over half of these isolates with EC50 values ranging from 7.8 to 122 μM. Among the tested compounds, the known dimer flueggenine D exhibited the best activity with an EC50 of 7.8 ± 0.8 μM.
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- 2016
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109. Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors
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Réjean Thomas, Esteban Martínez, Maureen Oliveira, Mark A. Wainberg, Bluma G. Brenner, Thibault Mesplède, Ruxandra-Ilinca Ibanescu, Federico García, Michel Roger, Olga Golubkov, and José Luis Santiago Blanco
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0301 basic medicine ,Microbiology (medical) ,Adult ,Male ,Genotyping Techniques ,Pyridones ,030106 microbiology ,Mutation, Missense ,Integrase inhibitor ,HIV Infections ,Drug resistance ,HIV Integrase ,Microbial Sensitivity Tests ,Biology ,Emtricitabine ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Resistance, Viral ,Oxazines ,medicine ,Missense mutation ,Humans ,Pharmacology (medical) ,HIV Integrase Inhibitors ,Treatment Failure ,Original Research ,Pharmacology ,Elvitegravir ,Cobicistat ,Middle Aged ,Virology ,3. Good health ,Integrase ,Infectious Diseases ,chemistry ,Dolutegravir ,biology.protein ,HIV-1 ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
OBJECTIVES Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained. PATIENT AND METHODS Genotypic analysis was performed on patients with virological failure (
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- 2016
110. Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity
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Vincent Cutillas, Mark A. Wainberg, Robert Fusco, Thibault Mesplède, and Kaitlin Anstett
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0301 basic medicine ,Microbiology (medical) ,Pyridones ,Mutant ,Mutation, Missense ,Drug resistance ,HIV Integrase ,Piperazines ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,law ,Drug Resistance, Viral ,Oxazines ,medicine ,Humans ,Pharmacology (medical) ,HIV Integrase Inhibitors ,Binding site ,Original Research ,Pharmacology ,biology ,Chemistry ,DNA ,Raltegravir ,Virology ,Recombinant Proteins ,Integrase ,030104 developmental biology ,Infectious Diseases ,Amino Acid Substitution ,Dolutegravir ,biology.protein ,Recombinant DNA ,HIV-1 ,Mutant Proteins ,Heterocyclic Compounds, 3-Ring ,medicine.drug ,Protein Binding - Abstract
Objectives The E157Q substitution in HIV-1 integrase (IN) is a relatively common natural polymorphism associated with HIV resistance to IN strand transfer inhibitors (INSTIs). Although R263K is the most common resistance substitution for the INSTI dolutegravir, an INSTI treatment-experienced individual recently failed dolutegravir-based therapy, with E157Q being the only resistance-associated change reported. Given that different resistance pathways can sometimes synergize to confer high levels of resistance to antiretroviral drugs, we studied the effects of E157Q in association with R263K. Because Glu157 is thought to lie within the binding site of HIV IN DNA binding inhibitors such as FZ41, we also evaluated DNA binding activity and resistance to IN inhibitors in the presence of E157Q. Methods Purified recombinant IN proteins were assessed in cell-free assays for their strand transfer and DNA binding activities. NL4.3 viral stocks harbouring IN mutations were generated and characterized in the presence and absence of IN inhibitors in tissue culture. Results E157Q alone had little if any effect on the biochemical activity of IN, and partially restored the activity of R263K-containing IN. The E157Q/R263K double viral mutant displayed infectiousness in culture equivalent to WT, while increasing resistance to dolutegravir by 10-fold compared with lower-level resistance associated with R263K alone. None of the mutations tested showed significant resistance to either raltegravir or FZ41. Conclusions This study shows that E157Q may act as a compensatory mutation for R263K. Since E157Q is a natural polymorphism present in 1%-10% of HIV-positive individuals, it may be of particular importance for patients receiving INSTI therapy.
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- 2016
111. Molecular Mechanism of Antagonism between the Y181C and E138K Mutations in HIV-1 Reverse Transcriptase
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Matthew McCallum, Maureen Oliveira, Eugene L. Asahchop, Peter K. Quashie, Hongtao Xu, Yudong Quan, Ying-Shan Han, and Mark A. Wainberg
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Anti-HIV Agents ,Immunology ,Mutation, Missense ,Etravirine ,Biology ,medicine.disease_cause ,Microbiology ,Chromatography, Affinity ,law.invention ,law ,Virology ,Vaccines and Antiviral Agents ,Drug Resistance, Viral ,Nitriles ,Escherichia coli ,medicine ,chemistry.chemical_classification ,Mutation ,DNA synthesis ,Reverse-transcriptase inhibitor ,Processivity ,Molecular biology ,HIV Reverse Transcriptase ,Recombinant Proteins ,Reverse transcriptase ,Pyridazines ,Kinetics ,Pyrimidines ,Enzyme ,chemistry ,Insect Science ,HIV-1 ,Recombinant DNA ,Electrophoresis, Polyacrylamide Gel ,medicine.drug - Abstract
Etravirine (ETR) is an expanded-spectrum nonnucleoside reverse transcriptase inhibitor (NNRTI) approved for use as an antiretroviral agent in treatment-experienced patients. Y181C and E138K in HIV-1 RT are among 20 different drug resistance mutations associated with ETR. However, E138K can be consistently selected by ETR when wild-type viruses but not viruses containing Y181C are grown in tissue culture. This study was carried out to evaluate any possible mechanisms that might explain antagonism between the Y181C and E138K mutations. Accordingly, we performed tissue culture studies to investigate the evolutionary dynamics of E138K in both a wild-type (WT) and a Y181C background. We also generated recombinant enzymes containing Y181C and E138K alone or in combination in order to study enzyme processivity, rates of processive DNA synthesis, enzyme kinetics, and susceptibility to ETR. We now show that the presence of the Y181C mutation prevented the emergence of E138K in cell culture and that the simultaneous presence of E138K and Y181C impaired each of enzyme activity, processivity, rate of processive DNA synthesis, and deoxynucleoside triphosphate (dNTP) affinity. The addition of E138K to Y181C also decreased the level of resistance to ETR compared to that obtained with Y181C alone.
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- 2012
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112. In vitro and structural evaluation of PL-100 as a potential second-generation HIV-1 protease inhibitor
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Peter K. Quashie, Bluma G. Brenner, Eugene L. Asahchop, Mark A. Wainberg, Cécile Tremblay, Maureen Oliveira, Jorge L. Martinez-Cajas, and Daniela Moisi
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Microbiology (medical) ,Biology ,Hydrophobic effect ,Structure-Activity Relationship ,HIV Protease ,HIV-1 protease ,medicine ,Humans ,HIV Protease Inhibitor ,Structure–activity relationship ,Pharmacology (medical) ,Darunavir ,Pharmacology ,chemistry.chemical_classification ,Sulfonamides ,Proteolytic enzymes ,HIV Protease Inhibitors ,Protease inhibitor (biology) ,Amino acid ,Infectious Diseases ,chemistry ,Biochemistry ,Mutation ,HIV-1 ,biology.protein ,Carbamates ,medicine.drug - Abstract
HIV-1 protease inhibitors (PIs) are key components of HIV therapy. PL-100 is a novel lysine sulphonamide that demonstrates potent antiviral activity against multiresistant HIV-1 strains as well as a higher genetic barrier for development of resistance mutations compared with first-generation PIs. In the present study, we compared the antiviral activity of PL-100 against HIV-1 subtype B with that of darunavir.We used tissue culture experiments to evaluate the in vitro development of resistance to PL-100 and tested the antiviral activity of several clinically approved PIs against PL-100-selected resistant variants. Structural modelling was also used to compare the binding of PL-100 and darunavir to the HIV-1 protease (PR) enzyme.PL-100-resistant variants that emerged within 8-48 weeks showed low- to high-level resistance (3.5- to 21.6-fold) to PL-100, but commonly retained susceptibility to darunavir, which, in contrast, did not select for resistance mutations over a period of 40 weeks. Structural modelling demonstrated that binding of PL-100 was predominantly based on polar interactions and delocalized hydrophobic interactions through its diphenyl groups, while darunavir has numerous interactions with PR that include hydrogen bonding to PR backbone oxygens at amino acid positions A28, D29 and D30 via di-tetrahydrofuran (di-THF) groups.Hydrogen-bonding contacts and the di-THF group in darunavir, as well as the hydrophobic nature of PL-100, contribute to PI binding and a high genetic barrier for resistance. Redesigning the structure of PL-100 to include a di-THF group might improve it.
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- 2012
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113. Maraviroc and Other HIV-1 Entry Inhibitors Exhibit a Class-Specific Redistribution Effect That Results in Increased Extracellular Viral Load
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Daniel A. Donahue, Maureen Oliveira, Randy Tressler, Susan M. Schader, Diane N. Singhroy, Richard D Sloan, Mark A. Wainberg, Susan P. Colby-Germinario, and Victor G. Kramer
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Cyclopropanes ,Benzylamines ,Receptors, CXCR4 ,Efavirenz ,Enfuvirtide ,Receptors, CCR5 ,Anti-HIV Agents ,viruses ,Biology ,Cyclams ,Antiviral Agents ,Virus ,Cell Line ,Raltegravir Potassium ,Maraviroc ,chemistry.chemical_compound ,Cyclohexanes ,HIV Fusion Inhibitors ,Heterocyclic Compounds ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,virus diseases ,Triazoles ,Viral Load ,Virus Internalization ,Raltegravir ,Virology ,HIV Envelope Protein gp41 ,HIV Reverse Transcriptase ,Peptide Fragments ,Pyrrolidinones ,Reverse transcriptase ,Benzoxazines ,Infectious Diseases ,chemistry ,Alkynes ,DNA, Viral ,HIV-1 ,RNA, Viral ,Viral load ,medicine.drug - Abstract
HIV entry inhibitors, such as maraviroc (MVC), prevent cell-free viruses from entering the cells. In clinical trials, patients who were treated with MVC often displayed viral loads that were above the limit of conventional viral load detection compared to efavirenz-based regimens. We hypothesize that viruses blocked by entry inhibitors may be redistributed to plasma, where they artificially increase viral load measurements compared to those with the use of antiretroviral drugs (ARVs) that act intracellularly. We infected PM-1 cells with CCR5-tropic HIV-1 BaL or CXCR4-tropic HIV-1 NL4-3 in the presence of inhibitory concentrations of efavirenz, raltegravir, enfuvirtide, maraviroc, and AMD3100, the latter three being entry inhibitors. Supernatant viral load, reverse transcriptase enzyme activity, and intracellular nucleic acid levels were measured at times up to 24 h postinfection. Infectivity of redistributed dual-tropic HIV-1 was assessed using TZM-bl cells. Extracellular viral load analysis revealed that entry inhibitor-treated cells had higher levels of virus in the supernatant than the cells treated with other ARVs at 8 h postinfection. By 24 h, the supernatant viral load was still higher for entry inhibitors than other ARVs. We observed a correlation between viral load and the step of entry inhibition. Dual-tropic virus infectivity was undiminished utilizing the CCR5 coreceptor following redistribution by CXCR4 entry inhibition. This in vitro model indicates that entry inhibitors exhibit a redistribution effect unseen with intracellular ARV drugs. Based on these results, the effectiveness of some entry inhibitors may be underestimated if plasma viral load is used as a sole indicator of clinical success.
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- 2012
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114. HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug
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Thibault Mesplède, Susan P. Colby-Germinario, Mark A. Wainberg, Susan M. Schader, Maureen Oliveira, Daniela Moisi, Peter K. Quashie, and Ruxandra-Ilinca Ibanescu
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Models, Molecular ,Genotype ,Anti-HIV Agents ,medicine.drug_class ,viruses ,In silico ,HIV Infections ,Drug resistance ,HIV Antibodies ,HIV Envelope Protein gp120 ,Biology ,Monoclonal antibody ,Genes, env ,Antiviral Agents ,law.invention ,Piperidines ,law ,Cell Line, Tumor ,Microbicide ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Amino Acid Sequence ,Protein Structure, Quaternary ,Pharmacology ,Polymorphism, Genetic ,virus diseases ,Virus Internalization ,Antibodies, Neutralizing ,Virology ,Entry inhibitor ,Infectious Diseases ,Docking (molecular) ,Pyrazines ,HIV-2 ,HIV-1 ,Mutagenesis, Site-Directed ,biology.protein ,Recombinant DNA ,Antibody ,Sequence Alignment ,medicine.drug - Abstract
BMS-599793 is a small molecule entry inhibitor that binds to human immunodeficiency virus type 1 (HIV-1) gp120, resulting in the inhibition of CD4-dependent entry into cells. Since BMS-599793 is currently considered a candidate microbicide drug, we evaluated its efficacy against a number of primary patient HIV isolates from different subtypes and circulating recombinant forms (CRFs) and showed that activity varied between ∼3 ρM and 7 μM at 50% effective concentrations (EC 50 s). Interestingly, CRF01_AE HIV-1 isolates consistently demonstrated natural resistance against this compound. Genotypic analysis of >1,600 sequences (Los Alamos HIV sequence database) indicated that a single amino acid polymorphism in Env, H375, may account for the observed BMS-599793 resistance in CRF01_AE HIV-1. Results of site-directed mutagenesis experiments confirmed this hypothesis, and in silico drug docking simulations identified a drug resistance mechanism at the molecular level. In addition, CRF01_AE viruses were shown to be resistant to multiple broadly neutralizing monoclonal antibodies. Thus, our results not only provide insight into how Env polymorphisms may contribute to entry inhibitor resistance but also may help to elucidate how HIV can evade some broadly neutralizing antibodies. Furthermore, the high frequency of H375 in CRF01_AE HIV-1, and its apparent nonoccurrence in other subtypes, could serve as a means for rapid identification of CRF01_AE infections.
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- 2012
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115. The Impact of HIV Genetic Polymorphisms and Subtype Differences on the Occurrence of Resistance to Antiretroviral Drugs
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Bluma G. Brenner and Mark A. Wainberg
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0303 health sciences ,Resistance (ecology) ,030306 microbiology ,business.industry ,Human immunodeficiency virus (HIV) ,Review Article ,Drug susceptibility ,Drug resistance ,Pharmacology ,medicine.disease_cause ,Phenotype ,Antiretroviral therapy ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Immunology ,medicine ,030212 general & internal medicine ,business - Abstract
The vast majority of reports on drug resistance deal with subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy (ART) on a worldwide basis. This notwithstanding the concept that naturally occurring polymorphisms among different non-B subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs) is supported by both enzymatic and virological data. These findings suggest that such polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays. It is mandatory that tools are optimized to assure accurate measurements of drug susceptibility in non-B subtypes and to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the choice of regimens to be used in second-line therapy. Although responsiveness to first-line therapy should not theoretically be affected by considerations of viral subtype and drug resistance, well-designed long-term longitudinal studies involving patients infected by viruses of different subtypes should be carried out.
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- 2012
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116. In Vitro Resistance Profile of the Candidate HIV-1 Microbicide Drug Dapivirine
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Maureen Oliveira, Susan P. Colby-Germinario, Susan M. Schader, Daniela Moisi, Mark A. Wainberg, and Ruxandra-Ilinca Ibanescu
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Sexual transmission ,Nevirapine ,Anti-HIV Agents ,Dapivirine ,Organophosphonates ,HIV Infections ,Microbial Sensitivity Tests ,Drug resistance ,Biology ,Pharmacology ,Antiviral Agents ,Microbicide ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Tenofovir ,Reverse-transcriptase inhibitor ,Adenine ,Stavudine ,Lamivudine ,Virology ,HIV Reverse Transcriptase ,Pyrimidines ,Infectious Diseases ,Mutation ,HIV-1 ,Reverse Transcriptase Inhibitors ,medicine.drug - Abstract
Antiretroviral-based microbicides may offer a means to reduce the sexual transmission of HIV-1. Suboptimal use of a microbicide may, however, lead to the development of drug resistance in users that are already, or become, infected with HIV-1. In such cases, the efficacy of treatments may be compromised since the same (or similar) antiretrovirals used in treatments are being developed as microbicides. To help predict which drug resistance mutations may develop in the context of suboptimal use, HIV-1 primary isolates of different subtypes and different baseline resistance profiles were used to infect primary cells in vitro in the presence of increasing suboptimal concentrations of the two candidate microbicide antiretrovirals dapivirine (DAP) and tenofovir (TFV) alone or in combination. Infections were ongoing for 25 weeks, after which reverse transcriptase genotypes were determined and scrutinized for the presence of any clinically recognized reverse transcriptase drug resistance mutations. Results indicated that suboptimal concentrations of DAP alone facilitated the emergence of common nonnucleoside reverse transcriptase inhibitor resistance mutations, while suboptimal concentrations of DAP plus TFV gave rise to fewer mutations. Suboptimal concentrations of TFV alone did not frequently result in the development of resistance mutations. Sensitivity evaluations for stavudine (d4T), nevirapine (NVP), and lamivudine (3TC) revealed that the selection of resistance as a consequence of suboptimal concentrations of DAP may compromise the potential for NVP to be used in treatment, a finding of potential relevance in developing countries.
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- 2012
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117. Insights into HIV-1 pathogenesis through drug discovery: 30 years of basic research and concerns for the future
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Mark A. Wainberg and Susan M. Schader
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medicine.medical_specialty ,Epidemiology ,Vaginal microbicide ,business.industry ,Drug discovery ,Human immunodeficiency virus (HIV) ,virus diseases ,Developing country ,Drug resistance ,medicine.disease_cause ,medicine.disease ,Microbicides for sexually transmitted diseases ,Pre-exposure prophylaxis ,Infectious Diseases ,Acquired immunodeficiency syndrome (AIDS) ,Immunology ,medicine ,Intensive care medicine ,business - Abstract
During the past 30 years, there have been huge breakthroughs in HIV research, the most important of which have been the development of antiretroviral drugs (ARVs). However, the ability of HIV to rapidly mutate and replicate has given rise to the development of drug resistance that threatens to reverse much of the progress that has been accomplished in HIV therapy. New research has shown that ARVs can even be used as preventive tools if administered to HIV vulnerable persons as tablets or vaginal microbicides in advance of possible HIV exposure. Furthermore, the successful treatment of HIV infected individuals can render HIV-positive individuals virtually non-infectious in many cases because the amount of virus in blood, tissues, and genital fluids is usually greatly reduced. This progress has led to a significant diminution in numbers of both infants who acquire HIV from their mothers as well as the sexual partners of infected, treated persons. The problem of drug resistance is likely to occur to greatest extent in some developing countries where lower quality drugs continue to be employed. It is ironic that such countries are those in which the numbers of new cases of HIV transmission are often the highest.
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- 2011
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118. Transmission Clustering Drives the Onward Spread of the HIV Epidemic Among Men Who Have Sex With Men in Quebec
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Daniela Moisi, Jonathan Weinberg, Michel Roger, Isabelle Hardy, James S. Koopman, Mark A. Wainberg, Bluma G. Brenner, David A. Stephens, Hugues Charest, and Reuven Turgel
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Male ,Time Factors ,Sexual Behavior ,Hiv epidemic ,HIV Infections ,Disease ,Biology ,Men who have sex with men ,Major Articles and Brief Reports ,Social support ,Risk-Taking ,Cluster Analysis ,Humans ,Immunology and Allergy ,Homosexuality, Male ,Hiv transmission ,Genetics ,Transmission (medicine) ,Quebec ,Social Support ,virus diseases ,Bayes Theorem ,Sequence Analysis, DNA ,Genes, pol ,Antiretroviral therapy ,Phylogeography ,Infectious Diseases ,Sexual behavior ,HIV-1 ,Demography - Abstract
There is a growing concern in the upsurge of human immunodeficiency virus (HIV) epidemics among men who have sex with men (MSM) in the era of highly active antiretroviral therapy (HAART) [1–7]. Phylogenetic analysis can clarify the structure of regional epidemics and provide a framework for an in-depth evaluation of the interplay of disease stage, social networks, and sexual behavior on HIV transmission [1, 2]. Co-clustering of half of primary infections in Quebec, where 75% of infected persons receive antiretroviral treatment, infers a disproportionate contribution of early-stage infection in HIV type 1 (HIV-1) transmission [1]. In this study, we have expanded our primary HIV (PHI) datasets from 2005 (n = 611) to 2009 (n = 1150) to evaluate cluster expansion over time. Our findings identified 3 characteristic transmission patterns: unique PHIs, small clusters (2–4 PHIs), and large clusters (5–31 PHIs). Large clusters represent the driving force of the Quebec epidemic, increasing from 25.2% of transmissions in 2005 to 39.1% in 2009. A phylodynamic approach investigated the relevance of cluster membership size to the spread of the HIV epidemic among MSM.
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- 2011
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119. Development of Antiretroviral Drug Resistance
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Mark A. Wainberg, Bluma G. Brenner, and Gerasimos J. Zaharatos
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Drug ,media_common.quotation_subject ,HIV Infections ,Drug resistance ,medicine.disease_cause ,Pharmacotherapy ,Drug Resistance, Viral ,Genetic variation ,Humans ,Medicine ,Clinical significance ,HIV Integrase Inhibitors ,Subtypes of HIV ,media_common ,Mutation ,Resistance (ecology) ,business.industry ,virus diseases ,HIV Protease Inhibitors ,General Medicine ,Virology ,Anti-Retroviral Agents ,Immunology ,HIV-1 ,Reverse Transcriptase Inhibitors ,Drug Therapy, Combination ,business - Abstract
fers among HIV variants. Indeed, we have limited knowledge of resistance muta tions in non-B subtypes of HIV type 1 (HIV-1) and their clinical relevance, despite the fact that more than 90% of patients with HIV-1 infection worldwide have non– subtype B variants of HIV-1. Most reports on drug resistance deal with subtype B infections in developed countries. Both enzymatic and virologic data indicate that naturally occurring polymorphisms among different HIV subtypes can influence HIV-1 susceptibility to individual antiretroviral drugs and the propensity of HIV to acquire certain resistance mutations. Furthermore, resistance pathways in different subtypes may affect drug cross-resistance and the potential use of specific secondline regimens. This concern may be increased in developing countries. Substantial natural genetic variation has led to the subclassification of HIV-1 group M (major) into nine subtypes (A through D, F through H, and J and K) and nu
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- 2011
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120. Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef
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Björn D. Kuhl, Daniel A. Donahue, Mark A. Wainberg, Richard D Sloan, Tamara Bar-Magen, and André Roland
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CD4-Positive T-Lymphocytes ,Transcription, Genetic ,viruses ,T cell ,Immunology ,Down-Regulation ,Gene Expression ,Biology ,Major histocompatibility complex ,Microbiology ,Cell Line ,Proviruses ,Transcription (biology) ,Virology ,Complementary DNA ,Gene expression ,medicine ,Humans ,Cytotoxic T cell ,nef Gene Products, Human Immunodeficiency Virus ,Histocompatibility Antigens Class I ,Virus-Cell Interactions ,Cell biology ,Chromatin ,medicine.anatomical_structure ,Cell culture ,Insect Science ,HIV-1 ,biology.protein - Abstract
Retroviruses are defined by the integration of their reverse-transcribed genome into host cell chromatin. This process enables transcription and translation of viral genes by host cells, ultimately resulting in new viral progeny. However, human immunodeficiency virus type 1 (HIV-1) gene transcription and translation can also occur prior to, or even in the absence of, viral integration (8, 53, 57), since unintegrated, reverse-transcribed viral cDNAs can also serve as a template for transcription (22). Three species of unintegrated HIV cDNAs are found in natural infections; these are linear reverse-transcribed cDNA, which is the template for integration, and 1-long terminal repeat (LTR) and 2-LTR circular forms, which are the products of autointegration or nonhomologous recombination and nonhomologous end-joining events of linear cDNAs, respectively (15, 26, 37). The circular cDNAs were long considered to be “dead end” products, which cannot serve as templates for integration, though it is now understood that unintegrated cDNA can be complemented by superinfecting virus to yield productive infection (17, 39, 53). Transcription of preintegrated HIV-1 cDNA can yield all classes of viral RNA transcripts (25, 37, 52); however, only the accessory and regulatory proteins Nef (18, 58), Tat (2, 14, 46), and Rev (22, 29) are translated in readily detectable amounts, and the full extent of the function of these proteins needs to be further characterized. Differences in transcription between integrated and unintegrated HIV-1 may be due to the fact that unintegrated HIV-1 cDNA is organized into chromatin structures, with histone modifications typical of silenced chromatin (23). Additionally, the low levels of Rev synthesized prior to integration may also limit the translation of unspliced viral RNA transcripts and ultimate expression of late gene products (58). Studies of integrase-defective HIV-1 mutants that bear mutations in the catalytic D(64)D(116)E(152) triad of integrase have been particularly useful in the study of preintegration transcription (18, 36). Indeed, patterns of transcription and translation arising from unintegrated DNA following infection with D116N mutated HIV-1 are identical to those observed from preintegrated viral DNA and in infections of T-cell lines, activated CD4+ T cells, resting T cells, and macrophages (25, 56, 58). Transcription and translation from unintegrated cDNA following use of integrase strand transfer inhibitors (INSTIs) are also indistinguishable from those seen with preintegrated virus or integrase-defective virus (21, 58). 2-LTR circles were previously proposed as a likely transcriptional template, as their levels were found to be elevated when viral integration was inhibited (14, 21). Moreover, a novel viral transcript spanning the LTR-LTR junction was detected, demonstrating that 2-LTR circles can act as a transcriptional template (7). In contrast, a recent study calculated that there were insufficient levels of 2-LTR circles to account for the numbers of cells bearing transcriptionally active preintegrated virus (22, 54, 55). Translation of nef, tat, and rev from preintegrated templates has been linked to a number of cellular effects which aid viral infection. For example, preintegration translation of tat and nef has been shown to increase the activation state of resting T cells, making them more amenable to productive infection (58). Preintegration translation of nef has been linked to reduced cell surface expression of CD4 in primary T cells and T cell lines (18, 36), and we have recently demonstrated that the CXCR4 and CCR5 coreceptors are also affected in this manner (45). In a study of macrophages, transcription of preintegrated HIV-1 cDNA was also linked to altered patterns of cytokine expression (25). CD8+ cytotoxic T-lymphocytes (CTLs) play a central role in the adaptive immune response to control HIV-1, as they recognize viral antigens presented through major histocompatibility complex class I (MHC-I) on infected cells and can limit infection either by direct lysis (5) or through release of inhibitory factors, such as RANTES, MIP-1 alpha, or MIP-1 beta (9). Therefore, modulation of cell surface expression of MHC-I is a common viral immune evasion strategy and avoids the presentation of viral antigens to CTLs, thereby preventing lysis of the infected cell (20). In the case of HIV-1, the virus-encoded protein Nef performs this function (11, 44). Nef downregulates MHC-I by forming a complex with the cytoplasmic tail of MHC-I and the clathrin adaptor AP-1 in the trans-Golgi network (TGN). This allows it to divert normal migration of newly synthesized MHC-I to the cell surface and instead targets it for endosomal degradation (28, 41, 47, 51). However, there is also some evidence that Nef may mediate accelerated endocytosis of MHC-I from the plasma membrane (28), and it has been suggested that cell type differences might also be important (24). HIV-1 Nef can mediate downregulation of the MHC-I/human leukocyte antigen (HLA) HLA-A and HLA-B allotypes, which are recognized by CTLs. In contrast, HIV-1 does not downregulate HLA-C and HLA-E, which is advantageous since a reduction in cell surface expression of these allotypes would lead to natural killer (NK) cell-mediated lysis, as NK cells respond to reduced MHC-I levels (10). We therefore hypothesized that the preintegration translation of nef has the capacity to modulate cell surface MHC-I expression. Here we show that preintegration transcription and translation of nef can modulate cell surface MHC-I in the same manner as when integration occurs. This suggests that transcription from preintegrated viral DNA can influence viral immune evasion even prior to viral integration into the host genome.
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- 2011
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121. Characterization of the E138K Resistance Mutation in HIV-1 Reverse Transcriptase Conferring Susceptibility to Etravirine in B and Non-B HIV-1 Subtypes
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Bluma G. Brenner, Maureen Oliveira, Mark A. Wainberg, Eugene L. Asahchop, Cécile Tremblay, Thomas d'Aquin Toni, and Daniela Moisi
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Efavirenz ,Nevirapine ,Anti-HIV Agents ,Molecular Sequence Data ,Etravirine ,HIV Infections ,Microbial Sensitivity Tests ,Drug resistance ,Biology ,Antiviral Agents ,Virus ,Cell Line ,chemistry.chemical_compound ,Drug Resistance, Viral ,Nitriles ,Genotype ,medicine ,Humans ,Pharmacology (medical) ,Amino Acid Sequence ,Pharmacology ,Resistance mutation ,Virology ,Molecular biology ,HIV Reverse Transcriptase ,Reverse transcriptase ,Pyridazines ,Pyrimidines ,Infectious Diseases ,chemistry ,Mutation ,HIV-1 ,Sequence Alignment ,medicine.drug - Abstract
We have selected for resistance to etravirine (ETR) and efavirenz (EFV) in tissue culture using three subtype B, three subtype C, and two CRF02_AG clinical isolates, grown in cord blood mononuclear cells. Genotypic analysis was performed at baseline and at various weeks of selection. Phenotypic resistance in regard to ETR, EFV, and nevirapine (NVP) was evaluated at weeks 25 to 30 for all ETR-selected viruses and in viral clones that contained specific resistance mutations that were inserted by site-directed mutagenesis into pNL-4.3 and AG plasmids. The results show that ETR selected mutations at positions V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y, and M230L and that E138K was the first of these to emerge in most instances. The time to the emergence of resistance was longer in the case of ETR (18 weeks) compared to EFV (11 weeks), and no differences in the patterns of emergent mutations could be documented between the B and non-B subtypes. Viral clones containing E138K displayed low-level phenotypic resistance to ETR (3.8-fold) and modestly impaired replication capacity (2-fold) compared to wild-type virus. ETR-selected virus showed a high degree of cross-resistance to NVP but not to EFV. We identified K101Q, E138K, V179E, V189I, G190E, and H221Y as mutations not included among the 17 currently recognized resistance-associated mutations for ETR.
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- 2011
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122. Complete inactivation of HIV-1 using photo-labeled non-nucleoside reverse transcriptase inhibitors
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Adan Rios, Theresa W. Fossum, Susan P. Colby-Germinario, Allan L. Goldstein, Dallas W. Anderson, Mark A. Wainberg, and Jorge R. Quesada
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Cancer Research ,Anti-HIV Agents ,Ultraviolet Rays ,T-Lymphocytes ,T cell ,Dapivirine ,Biology ,Peripheral blood mononuclear cell ,Nucleoside Reverse Transcriptase Inhibitor ,Immune system ,Virology ,Ultraviolet light ,medicine ,Humans ,Cells, Cultured ,Microbial Viability ,Photosensitizing Agents ,Reverse-transcriptase inhibitor ,Molecular biology ,HIV Reverse Transcriptase ,Reverse transcriptase ,Pyrimidines ,Infectious Diseases ,medicine.anatomical_structure ,Leukocytes, Mononuclear ,Reverse Transcriptase Inhibitors ,medicine.drug - Abstract
We demonstrate that a photo-labeled derivative of the non-nucleoside reverse transcriptase inhibitor (NNRTI) dapivirine termed DAPY, when used together with exposure to ultraviolet light, was able to completely and irreversibly inactivate both HIV-1 RT activity as well as infectiousness in each of a T cell line and peripheral blood mononuclear cells. Control experiments using various concentrations of DAPY revealed that a combination of exposure to ultraviolet light together with use of the specific, high affinity photo-labeled compound was necessary for complete inactivation to occur. This method of HIV RT inactivation may have applicability toward preservation of an intact viral structure and warrants further investigation in regard to the potential of this approach to elicit a durable, broad protective immune response.
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- 2011
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123. Tissue culture drug resistance analysis of a novel HIV-1 protease inhibitor termed PL-100 in non-B HIV-1 subtypes
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Jorge L. Martinez-Cajas, Serge Dandache, Eugene L. Asahchop, Maureen Oliveira, Daniela Moisi, Mark A. Wainberg, Thomas d'Aquin Toni, Michel Ntemgwa, Bluma G. Brenner, Brent Richard Stranix, and Cécile Tremblay
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Anti-HIV Agents ,Mutation, Missense ,Microbial Sensitivity Tests ,Drug resistance ,Biology ,Recombinant virus ,medicine.disease_cause ,Virus ,Tissue culture ,HIV Protease ,HIV-1 protease ,Virology ,Drug Resistance, Viral ,medicine ,Humans ,Protease inhibitor (pharmacology) ,Pharmacology ,chemistry.chemical_classification ,Sulfonamides ,Mutation ,virus diseases ,HIV Protease Inhibitors ,Enzyme ,Amino Acid Substitution ,chemistry ,HIV-1 ,biology.protein ,Carbamates - Abstract
PL-100 is a novel HIV-1 protease inhibitor (PI) that maintains activity against viruses that are resistant to other PIs. To further characterize this compound, we used it to select for drug resistance in tissue culture, using two non-B HIV-1 subtypes, viz. subtype C and a CRF01_AE recombinant virus. PL-100 selected for both minor and major PI resistance mutations along either of two distinct pathways. One of these involved the V82A and L90M resistance mutations while the other involved a mutation at position T80I, with other mutations being observed at positions M46I/L, I54M, K55R, L76F, P81S and I85V. The resistance patterns in both subtype C and CRF01_AE were similar and an accumulation of at least three mutations in the flap and active sites were required in each case for high-level resistance to occur, demonstrating that PL-100 has a high genetic barrier against the development of drug resistance.
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- 2010
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124. HIV-1 Protease Codon 36 Polymorphisms and Differential Development of Resistance to Nelfinavir, Lopinavir, and Atazanavir in Different HIV-1 Subtypes
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Daniela Moisi, Mark A. Wainberg, Susan M. Schader, Jorge-Luis Martinez-Cajas, Irene Lisovsky, and Maureen Oliveira
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Genotype ,Anti-HIV Agents ,Pyridines ,viruses ,medicine.medical_treatment ,Atazanavir Sulfate ,HIV Infections ,Pyrimidinones ,Biology ,Antiviral Agents ,Lopinavir ,Virus ,Cell Line ,HIV Protease ,HIV-1 protease ,medicine ,Humans ,Pharmacology (medical) ,Codon ,Cells, Cultured ,Pharmacology ,Genetics ,Nelfinavir ,Polymorphism, Genetic ,Protease ,virus diseases ,Resistance mutation ,Virology ,Atazanavir ,Infectious Diseases ,Viral replication ,HIV-1 ,biology.protein ,Viral disease ,Oligopeptides ,medicine.drug - Abstract
The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
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- 2010
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125. The M230L Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutation in HIV-1 Reverse Transcriptase Impairs Enzymatic Function and Viral Replicative Capacity
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Mark A. Wainberg, Yudong Quan, Hongtao Xu, Tamara Bar-Magen, Maureen Oliveira, and Susan M. Schader
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Efavirenz ,Nevirapine ,Anti-HIV Agents ,Mutant ,Etravirine ,Virus Replication ,Antiviral Agents ,Cell Line ,chemistry.chemical_compound ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,Base Sequence ,Reverse-transcriptase inhibitor ,Chemistry ,virus diseases ,Resistance mutation ,Virology ,Molecular biology ,HIV Reverse Transcriptase ,Recombinant Proteins ,Reverse transcriptase ,Infectious Diseases ,Viral replication ,DNA, Viral ,Mutation ,HIV-1 ,Reverse Transcriptase Inhibitors ,medicine.drug - Abstract
The M230L mutation in HIV-1 reverse transcriptase (RT) is associated with resistance to first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The present study was designed to determine the effects of M230L on enzyme function, viral replication capacity (RC), and the extent to which M230L might confer resistance to the second-generation NNRTI etravirine (ETR) as well as to the first-generation NNRTIs efavirenz (EFV) and nevirapine (NVP). Phenotyping assays with TZM-bl cells confirmed that M230L conferred various degrees of resistance to each of the NNRTIs tested. Recombinant viruses containing M230L displayed an 8-fold decrease in RC compared to that of the parental wild-type (WT) virus. Recombinant HIV-1 WT and M230L mutant RT enzymes were purified; and both biochemical and cell-based phenotypic assays confirmed that M230L conferred resistance to each of EFV, NVP, and ETR. RT that contained M230L was also deficient in regard to each of minus-strand DNA synthesis, both DNA- and RNA-dependent polymerase activities, processivity, and RNase H activity, suggesting that this mutation contributes to diminished viral replication kinetics.
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- 2010
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126. Reconsidering the lifetime deferral of blood donation by men who have sex with men
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Norbert Gilmore, Talia Shuldiner, Karine Dahl, and Mark A. Wainberg
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Male ,Canada ,medicine.medical_specialty ,Time Factors ,Letter ,media_common.quotation_subject ,Human immunodeficiency virus (HIV) ,Blood Donors ,HIV Infections ,medicine.disease_cause ,Men who have sex with men ,medicine ,Humans ,Homosexuality ,Homosexuality, Male ,Deferral ,media_common ,Gynecology ,Risk Management ,business.industry ,virus diseases ,General Medicine ,Blood donor ,Family medicine ,Donation ,Female ,business ,Developed country ,Analysis ,Male Homosexuality - Abstract
The decision by blood agencies in many developed countries to defer the donation of blood by men who have sex with men was justified when it was first implemented, in 1983, given that there was no effective mechanism to screen for HIV infection until screening for HIV antibodies became available in
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- 2010
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127. Multi-Low-Dose Mucosal Simian Immunodeficiency Virus SIVmac239 Challenge of Cynomolgus Macaques Immunized with 'Hyperattenuated' SIV Constructs
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Paul Sandstrom, Yongjun Guan, Jocelyn Fournier, Rick Pilon, Bing Li, Mark A. Luscher, Kelly S. MacDonald, Mark A. Wainberg, Monique Parenteau, and David O. Willer
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Male ,animal diseases ,viruses ,Immunology ,Simian Acquired Immunodeficiency Syndrome ,Enzyme-Linked Immunosorbent Assay ,medicine.disease_cause ,Microbiology ,Virus ,Interferon-gamma ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Lymphocytes ,Viremia ,Attenuated vaccine ,biology ,Immunogenicity ,Vaccination ,SAIDS Vaccines ,virus diseases ,Simian immunodeficiency virus ,Vaccine efficacy ,biology.organism_classification ,Macaca fascicularis ,Insect Science ,Lentivirus ,Disease Progression ,RNA, Viral ,Simian Immunodeficiency Virus ,Viral load - Abstract
To date, the most promising approach to inducing sterilizing immunity in the macaque model has been through the use of live attenuated virus (LAV) vaccines based on simian immunodeficiency virus (SIV). A major advantage of an attenuated virus strategy for the development of a human immunodeficiency virus (HIV) vaccine is the ability of attenuated viruses to induce broad and persistent immunity (29, 51). In particular, SIV strains engineered with deletions of nef (SIVΔnef) have afforded the most significant protection upon challenge with pathogenic SIV (13, 14, 29, 60, 65, 72). Numerous SIV-derived live attenuated vaccine models have been developed, many of which employ deletions in the viral accessory genes (3, 12, 14, 15, 25, 29, 30, 53, 64, 72). In many cases, vaccinations have been shown to substantially decrease viral burden during the acute phase of infection, maintain low to undetectable levels of virus during the chronic phase of infection, and limit the progression to AIDS. Although promising, a major caveat to the live attenuated virus vaccine approach is the potential for compensatory reversion and the observations that incompletely attenuated viruses may harbor residual pathogenicity (5, 10, 14). Even SIV constructs containing multiple deletions in nef, vpr, and the negative regulatory element (NRE) can cause AIDS-like disease in adult macaques and particularly in neonates (4, 5, 27, 53). This may be analogous to some human long-term nonprogressors infected by nef-deleted HIV variants in whom a slowly increasing viral burden has been accompanied by disease progression (22, 34, 37). Additional mutations can be engineered into vaccine vectors to generate highly attenuated viruses, but this often comes at the expense of their protective efficacy (8, 23, 30). We previously made two series of novel live attenuated SIV vaccine models (25) in which the simplified SIV constructs retain all the structural viral proteins but have inactivating mutations for all viral accessory genes. These constructs retain significant antigenicity, without the pathogenic effects associated with accessory viral factors, thus limiting or eliminating the potential for reversion (25). Whether administered parenterally or mucosally, conventional challenge trials in macaques have often utilized artificially high single-dose inocula in an effort to ensure that most, if not all, of the naive or placebo-immunized animal subjects become infected following a single exposure. The rationale for using a single massive challenge has been reconsidered in light of the possibility that vaccines with protective efficacy under physiologic challenge conditions may not identified. This practice is now being replaced by an approach designed to better approximate the relatively low in vivo acquisition rates following a single sexual exposure to HIV (21, 45, 69) and should provide a more realistic assessment of vaccine efficacy in “real-world” situations. Importantly, recent studies using this approach have demonstrated viremia of magnitude and kinetics comparable to that seen following single high-dose mucosal inocula (47), and this approach has been used successfully in more recent challenge trials (31, 70). Here we are assessing the safety, immunogenicity, and protective efficacy of two hyperattenuated SIV vaccine candidates following a multi-low-dose intrarectal challenge with highly pathogenic SIVmac239 in the cynomolgus macaque model. SIV-specific humoral immune responses were assessed at various time points postvaccination and postchallenge by Western blotting. Cellular immunogenicity was monitored by evaluation of peripheral T-cell responses (via gamma interferon [IFN-γ] enzyme-linked immunospot [ELISPOT] assay) following stimulation with peptide pools spanning the entire SIVmac239 proteome. The protective efficacy of the different vaccine candidates was assessed by classical endpoints, such as quantitative analysis of plasma viral load, quantitative immunophenotyping of lymphocytes, and clinical markers of disease progression. Even using extremely attenuated SIV constructs with only minimal evidence of replication, a modest immune response that can impact long-term disease progression is generated.
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- 2010
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128. Canadian Consensus Guidelines for the Optimal Use of Maraviroc in the Treatment of HIV-Infected Adults
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Anita Rachlis, Sharon Walmsley, Cécile Tremblay, Stephen D. Shafran, Richard N. Lalonde, Marianne Harris, and Mark A. Wainberg
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Microbiology (medical) ,medicine.medical_specialty ,Human immunodeficiency virus (HIV) ,Etravirine ,Infectious and parasitic diseases ,RC109-216 ,CCR5 receptor antagonist ,medicine.disease_cause ,Appropriate use ,Microbiology ,Special Article ,chemistry.chemical_compound ,Pharmacotherapy ,Hiv infected ,Health care ,Medicine ,Maraviroc ,business.industry ,virus diseases ,QR1-502 ,Infectious Diseases ,chemistry ,Family medicine ,Immunology ,business ,medicine.drug - Abstract
BACKGROUND AND OBJECTIVES: A Canadian group, consisting of six physicians and an HIV researcher with significant experience and knowledge in HIV management, reviewed the available data and developed guidelines for Canadian health care providers (who treat HIV infection) on the appropriate use of maraviroc (UK-427,857) in HIV-infected adults.METHODS: Evidence from the published literature and conference presentations, as well as the expert opinions of the group members were considered and evaluated to develop the recommendations. Feedback on the draft recommendations was obtained from this core group, as well as from four other physicians across Canada with expertise in HIV treatment and experience with the use of maraviroc. The final recommendations represent the core group’s consensus agreement once all feedback was considered.RESULTS/CONCLUSIONS: Recommendations were developed to guide physicians and other health care providers in the optimal use of maraviroc. The recommendations were considered in light of the fact that the decision to include maraviroc in an antiretroviral regimen depends not only on issues that concern all antiretroviral agents, such as efficacy, safety, resistance and drug interactions, but also on the issue of viral tropism, which is unique to maraviroc and other CCR5 inhibitors.
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- 2010
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129. Resistance profile of the new nucleoside reverse transcriptase inhibitor apricitabine
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Pedro Cahn and Mark A. Wainberg
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Microbiology (medical) ,Anti-HIV Agents ,Apricitabine ,Mutation, Missense ,HIV Infections ,Drug resistance ,Emtricitabine ,Deoxycytidine ,Nucleoside Reverse Transcriptase Inhibitor ,immune system diseases ,Drug Resistance, Viral ,Humans ,Medicine ,Pharmacology (medical) ,Pharmacology ,Reverse-transcriptase inhibitor ,business.industry ,virus diseases ,Lamivudine ,Resistance mutation ,Virology ,HIV Reverse Transcriptase ,Reverse transcriptase ,Infectious Diseases ,HIV-1 ,business ,medicine.drug - Abstract
Apricitabine is a novel deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI) currently in clinical development for the treatment of HIV infection. Apricitabine shows antiviral activity in vitro against HIV-1 strains and clinical isolates with mutations in the reverse transcriptase that confer resistance to other NRTIs, including M184V, thymidine analogue mutations (TAMs), nucleoside-associated mutations such as L74V and certain mutations at codon 69. Apricitabine has shown activity in treatment-experienced HIV-1-infected patients with NRTI resistance (with M184V and up to five TAMs) as well as in treatment-naive patients. Resistance to apricitabine is slow to develop in vitro and there has been little evidence of development of resistance to apricitabine in clinical use thus far, including patients receiving apricitabine for up to 48 weeks. The resistance profile of apricitabine suggests there is a low potential for cross-resistance with the currently available NRTIs and, thus, apricitabine may provide a treatment option for treatment-experienced HIV-1-infected patients with resistance to other NRTIs. In particular, the activity of apricitabine in the presence of the M184V mutation, which confers high-level resistance to lamivudine and emtricitabine, lends it to being used as a replacement for deoxycytidine analogues in patients who have failed treatment with lamivudine or emtricitabine.
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- 2009
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130. HIV inactivation by cross-linking of photo-labeled anti-retroviral compounds with HIV reverse transcriptase
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Adan Rios, Jorge R. Quesada, Mark A. Wainberg, Dallas W. Anderson, Allan L. Goldstein, Theresa W. Fossum, and Susan P. Colby-Germinario
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genetic structures ,Cell Survival ,Ultraviolet Rays ,HIV Core Protein p24 ,Human immunodeficiency virus (HIV) ,HIV Infections ,Photoaffinity Labels ,medicine.disease_cause ,Virus ,Substrate Specificity ,Inhibitory Concentration 50 ,Cell Line, Tumor ,medicine ,Humans ,AIDS Vaccines ,chemistry.chemical_classification ,General Veterinary ,General Immunology and Microbiology ,biology ,RNA-Directed DNA Polymerase ,Public Health, Environmental and Occupational Health ,Nucleotidyltransferase ,biology.organism_classification ,Virology ,Molecular biology ,HIV Reverse Transcriptase ,Reverse transcriptase ,Cross-Linking Reagents ,Infectious Diseases ,Enzyme ,chemistry ,Covalent bond ,Lentivirus ,HIV-1 ,Reverse Transcriptase Inhibitors ,Virus Inactivation ,Molecular Medicine ,sense organs - Abstract
We describe a new method for the development of a preventive inactivated-HIV vaccine, based on photo-inactivation of HIV reverse transcriptase (RT), which preserves both the conformational and functional integrity of viral surface proteins. The RT of HIV-1 was selectively targeted for inactivation using a photo-labeled compound with specific affinity for HIV-1 RT. The photo-labeled virions were then exposed to UV light causing the photo-labeled compound to form a covalent bond cross-linking the photo-active compound to RT. Replication capacity of the treated virions was significantly reduced when compared to controls suggesting that exposure of treated virions to UV light had caused a stable interaction of RT and the photo-labeling compound.
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- 2009
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131. Prevalence of the K65R resistance reverse transcriptase mutation in different HIV-1 subtypes in Israel
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Eduardo Shahar, Eugene Katchman, Michal Katzir, Boaz Avidor, Shimon Pollack, Rivka Kessner, Gamal Hassoun, Natasha Matus, Eynat Kedem, Mark A. Wainberg, and Dan Turner
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Adult ,Male ,Genotype ,Anti-HIV Agents ,viruses ,Mutation, Missense ,HIV Infections ,Drug resistance ,Biology ,Virus ,Young Adult ,immune system diseases ,Abacavir ,Virology ,Drug Resistance, Viral ,Prevalence ,medicine ,Animals ,Humans ,Missense mutation ,Israel ,Didanosine ,Aged ,Retrospective Studies ,virus diseases ,Sequence Analysis, DNA ,Middle Aged ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,HIV Reverse Transcriptase ,Reverse transcriptase ,Infectious Diseases ,Lentivirus ,HIV-1 ,Reverse Transcriptase Inhibitors ,Female ,medicine.drug - Abstract
The K65R mutation in HIV-1 reverse transcriptase (RT) can be selected by the RT inhibitors tenofovir (TDF), abacavir (ABC), and didanosine (DDI). Recently, in vitro studies have shown that K65R is selected in tissue culture more rapidly with subtype C than subtype B viruses. The prevalence of K65R in viruses sequenced at the Tel-Aviv AIDS Center was evaluated. This study analyzed retrospectively sequences from 1999 to 2007 in patients treated with TDF, ABC, and/or DDI and compared rates of mutational prevalence between subtypes. Fisher's exact test was used to determine statistical significance. Forty-four sequences from patients treated with the three above-cited drugs were analyzed. Subtypes A (n = 1), CRF01_AE (n = 4), CRF02_AG (n = 2), B (n = 21), C (n = 11), D (n = 1), F (n = 3), and G (n = 1) were represented. Seven non-B viruses had the K65R mutation, which was only found in one subtype B virus. Of these seven samples four were subtype C, one was subtype CRF01_AE, and two were subtype CRF02_AG. None of the eight viruses with K65R harbored thymidine analogue mutations. In this study, non-subtype B viruses possessed the K65R mutation at higher incidence than subtype B viruses. Subtype C viruses may be especially prone to develop this mutation. Larger studies are needed to confirm these data. Efforts should be intensified to understand better differences in drug resistance between various HIV subtypes.
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- 2009
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132. Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2
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Thomas d'Aquin Toni, Ricardo Jorge Camacho, Michel L. Ntemgwa, Bluma G. Brenner, and Mark A. Wainberg
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Pharmacology ,biology ,RNA-Directed DNA Polymerase ,HIV Protease Inhibitors ,Drug resistance ,biology.organism_classification ,medicine.disease ,Antiviral Agents ,Virology ,Virus ,Infectious Diseases ,Immune system ,HIV Protease ,Acquired immunodeficiency syndrome (AIDS) ,Drug Resistance, Viral ,HIV-2 ,Lentivirus ,Immunology ,medicine ,Humans ,HIV Protease Inhibitor ,Pharmacology (medical) ,Minireview ,Viral disease ,Sida - Abstract
Scientists established long ago that human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS ([4][1], [30][2], [48][3]). HIV is known to severely damage the immune system by selectively infecting T-helper (CD4+) lymphocytes. This can lead to serious infections by agents that would
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- 2009
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133. Template Usage Is Responsible for the Preferential Acquisition of the K65R Reverse Transcriptase Mutation in Subtype C Variants of Human Immunodeficiency Virus Type 1
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Daniela Moisi, Maureen Oliveira, Mark A. Wainberg, Bluma G. Brenner, Dimitrios Coutsinos, Cédric F. Invernizzi, and Hongtao Xu
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viruses ,Immunology ,Mutation, Missense ,C-DNA ,Biology ,medicine.disease_cause ,Microbiology ,Virus ,chemistry.chemical_compound ,Virology ,Vaccines and Antiviral Agents ,medicine ,Humans ,Mutation ,DNA synthesis ,RNA-Directed DNA Polymerase ,Templates, Genetic ,Nucleotidyltransferase ,Molecular biology ,HIV Reverse Transcriptase ,Reverse transcriptase ,Amino Acid Substitution ,chemistry ,Insect Science ,DNA, Viral ,HIV-1 ,DNA - Abstract
We propose that a nucleotide template-based mechanism facilitates the acquisition of the K65R mutation in subtype C human immunodeficiency virus type 1 (HIV-1). Different patterns of DNA synthesis were observed using DNA templates from viruses of subtype B or C origin. When subtype C reverse transcriptase (RT) was employed to synthesize DNA from subtype C DNA templates, preferential pausing was seen at the nucleotide position responsible for the AAG-to-AGG K65R mutation. This did not occur when the subtype B RT and template were used. Template factors can therefore increase the probability of K65R development in subtype C HIV-1.
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- 2009
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134. Antiviral drug development: progress and pitfalls
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Richard D Sloan, Dimitrios Coutsinos, and Mark A. Wainberg
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Hepatitis virus ,Topical microbicides ,Drug development ,business.industry ,Drug discovery ,medicine.drug_class ,viruses ,Virology ,Medicine ,Antiviral drug ,business ,HIV therapy - Abstract
Conferences on Antiviral Research present a wealth of new information on novel drug development and the 21st annual meeting, held in Montreal between 13–17 April 2008, was no exception. The sessions topics included novel targets for HIV therapy, respiratory and emerging viruses, hepatitis viruses, clinical update on antiviral drugs, retroviruses, and herpes- and poxviruses, among others. In addition, there were a number of themed poster sessions dealing with each of the above areas, as well as novel methods for antiviral analysis, topical microbicides, medicinal chemistry, animal models, veterinary viruses and assorted viral agents. Each of these sessions were well organized and provoked thoughtful discussions. The session on novel targets for HIV therapy featured cutting-edge lectures on interactions between viral proteins and cellular factors. This work has the potential to lead to novel drug discovery as does that on peptide-based approaches to prevent replication of influenza viruses and the development of novel compounds that interfere with the neuraminidase enzymes of both influenza and parainfluenza viruses. Other areas of focus included novel approaches aimed at heightening immune effector mechanisms and the development of gene therapy strategies for certain types of viral infection. Of course, the development of compounds directed at numerous hepatitis C targets also featured prominently at the meeting.
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- 2008
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135. Discrepancies in Assignment of Subtype/Recombinant Forms by Genotyping Programs for HIV Type 1 Drug Resistance Testing May Falsely Predict Superinfection
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Daniela Moisi, M. John Gill, Mark A. Wainberg, Michel Ntemgwa, and Bluma G. Brenner
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Male ,Anti-HIV Agents ,Immunology ,HIV Infections ,Computational biology ,Drug resistance ,medicine.disease_cause ,Acquired immunodeficiency syndrome (AIDS) ,Virology ,Drug Resistance, Viral ,medicine ,Humans ,False Positive Reactions ,Typing ,Genotyping ,biology ,Genetic Variation ,biology.organism_classification ,medicine.disease ,Subtyping ,Infectious Diseases ,Superinfection ,Lentivirus ,HIV-1 ,Viral disease ,Sequence Analysis - Abstract
With the growing diversity of the HIV pandemic, routine genotyping is an important tool for monitoring viral subtype as well as drug resistance. In this regard, numerous subtyping tools and drug resistance algorithms are available online. However, there are discrepancies in the use of these online tools in the designation of HIV-1 subtypes or recombinant forms that may have an impact on drug susceptibility profiles. Indeed, inconsistencies in some of these tools may lead to a false designation of dual infection and/or superinfection. In this case study, we evaluated the sequence diversity of an infection that was referred to us as a potential case of superinfection as a result of variations in designation of subtype. We evaluated sequences using five different online tools and finally determined by phylogenetic analysis that the sequence was a unique A1/C intersubtype recombinant at baseline and not a case of superinfection.
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- 2008
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136. Antiretroviral Therapy
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Jorge L. Martinez-Cajas and Mark A. Wainberg
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Drug ,media_common.quotation_subject ,HIV Infections ,Context (language use) ,Bioinformatics ,Emtricitabine ,Drug Administration Schedule ,Zidovudine ,Drug Resistance, Multiple, Viral ,Abacavir ,Antiretroviral Therapy, Highly Active ,Humans ,Medicine ,Pharmacology (medical) ,Protease inhibitor (pharmacology) ,Treatment Failure ,media_common ,biology ,business.industry ,Patient Selection ,Stavudine ,biology.organism_classification ,Virology ,Anti-Retroviral Agents ,Mutation ,Lentivirus ,HIV-1 ,business ,medicine.drug - Abstract
In the second decade of highly active antiretroviral therapy, drug regimens offer more potent, less toxic and more durable choices. However, strategies addressing convenient sequential use of active antiretroviral combinations are rarely presented in the literature. Studies have seldom directly addressed this issue, despite it being a matter of daily use in clinical practice. This is, in part, because of the complexity of HIV-1 resistance information as well as the complexity of designing these types of studies. Nevertheless, several principles can effectively assist the planning of antiretroviral drug sequencing. The introduction of tenofovir disoproxil fumarate, abacavir and emtricitabine into current nucleoside backbone options, with each of them selecting for an individual pattern of resistance mutations, now permits sequencing in the context of previously popular thymidine analogues (zidovudine and stavudine). Similarly, newer ritonavir-boosted protease inhibitors could potentially be sequenced in a manner that uses the least cross-resistance prone protease inhibitor at the start of therapy, while leaving the most cross-resistance prone drugs for later, as long as there is rationale to employ such a compound because of its utility against commonly observed drug-resistant forms of HIV-1.
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- 2008
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137. Gender and the Use of Antiretroviral Treatment in Resource-Constrained Settings: Findings from a Multicenter Collaboration
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Eric Balestre, Nicola Low, Matthias Egger, Ken Freedberg, Denis Nash, Suely H. Tuboi, Eric Delaporte, Brigitte Bazin, Christian Laurent, Margaret Pascoe, Mauro Schechter, Tony Harries, Mina C. Hosseinipour, David R. Bangsberg, Catherine Seyler, Ruedi Lüthy, François Dabis, Paolo G. Miotti, Kamal Marhoum El Filali, Martin W. G. Brinkhof, Claire Graber, Winstone Nyandiko Mokaya, James McIntyre, Christopher Bailey, Catherine Hankins, Robin Wood, Diana Dickinson, Silvester Kimaiyo, Kathy Anastos, Nagalingeswaran Kumarasamy, Besigin Tonwe-Gold, Wafaa El-Sadr, Martin Brinkhof, Larry Pepper, Charles Kabugo, Paula Braitstein, John E. Sidle, Jack Whitescarver, Ernest Ekong, Mana Khongphatthanayothin, Charles F. Gilks, Stefaan Van Der Borght, Franck Olivier Ba-Gomis, Timothy Meade, Eduardo Sprinz, Kevin M. De Cock, Eugène Messou, Zackie Achmat, Adama Ndir, Ralf Weigel, Jennipher Chisanga, Mark A. Wainberg, Papa Salif Sow, Margaret T May, Siaka Toure, David Bangsberg, Jonathan A C Sterne, Elly Katabira, Olivia Keiser, Helene Gayle, Andrew Boulle, and Sam Phiri
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Adult ,Male ,Asia ,Social Values ,Anti-HIV Agents ,Resource constrained ,Human immunodeficiency virus (HIV) ,Primary health care ,Developing country ,HIV Infections ,World Health Organization ,medicine.disease_cause ,Health Services Accessibility ,Antiretroviral Therapy, Highly Active ,medicine ,Antiretroviral treatment ,Humans ,Sex Distribution ,Developing Countries ,Primary Health Care ,business.industry ,Gender distribution ,virus diseases ,General Medicine ,Antiretroviral therapy ,Latin America ,Multicenter study ,Africa ,Female ,business ,Clinical psychology ,Demography - Abstract
To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART.The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration.Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation.Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.
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- 2008
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138. Variations in Reverse Transcriptase and RNase H Domain Mutations in Human Immunodeficiency Virus Type 1 Clinical Isolates Are Associated with Divergent Phenotypic Resistance to Zidovudine
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Richard G. Lalonde, Daniela Moisi, Bluma G. Brenner, Mark A. Wainberg, Michel L. Ntemgwa, Valeria Micheli, and Maureen Oliveira
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Apricitabine ,Molecular Sequence Data ,Ribonuclease H ,Organophosphonates ,HIV Infections ,Biology ,medicine.disease_cause ,Antiviral Agents ,Deoxycytidine ,Virus ,Nucleoside Reverse Transcriptase Inhibitor ,Drug Resistance, Multiple, Viral ,immune system diseases ,medicine ,Humans ,Pharmacology (medical) ,Amino Acid Sequence ,Tenofovir ,RNase H ,Pharmacology ,Genetics ,Mutation ,Sequence Homology, Amino Acid ,Nucleoside analogue ,Adenine ,Genetic Variation ,virus diseases ,RNA-Directed DNA Polymerase ,Resistance mutation ,Virology ,Reverse transcriptase ,Phenotype ,Infectious Diseases ,HIV-1 ,biology.protein ,Zidovudine ,medicine.drug - Abstract
Mutations in the RNase H domain of human immunodeficiency virus type 1 RT have been reported to cause resistance to zidovudine (ZDV) in vitro. However, very limited data on the in vivo relevance of these mutations in patients exist to date. This study was designed to determine the relationship between mutations in the RNase H domain and viral susceptibility to nucleoside analogues. Viruses harboring complex thymidine analogue mutation (TAM) and nucleoside analogue mutation (NAM) profiles were evaluated for their phenotypic susceptibilities to ZDV, tenofovir (TNF), and the nonapproved nucleoside reverse transcriptase inhibitors (NRTIs) β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (Reverset), β-d-5-fluorodioxolane-cytosine, and apricitabine. As controls, viruses from NRTI-naïve patients were also studied. ThepolRT region (codons 21 to 250) of the viruses were sequenced and evaluated for mutations in the RNase H domain (codons 441 to 560) and the connection domain (codons 289 to 400). The results showed that viruses from patients failing multiple NRTI-containing regimens had distinct TAM and NAM profiles that conferred various degrees of resistance to ZDV (0.9- to >300-fold). Sequencing of the RNase H domain identified five positions (positions 460,468, 483, 512, and 519) at which extensive amino acid polymorphisms common in both wild-type viruses and viruses from treated patients were identified. No mutations were observed at positions 539 and 549, which have previously been associated with ZDV resistance. Mutations in the RNase H domain did not appear to correlate with the levels of phenotypic resistance to ZDV. Although some mutations were also observed in the connection domain, the simultaneous presence of the L74V and M184V mutations was the most significant determinant of phenotypic resistance to ZDV in patients infected with viruses with TAMs.
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- 2007
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139. In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1
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Jonathan M. Schapiro, Jocelyn Yelle, Jinzi J. Wu, Serge Dandache, Guy Sevigny, Mark A. Wainberg, Brent Richard Stranix, and Neil Parkin
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Genotype ,Cell Survival ,Microbial Sensitivity Tests ,Biology ,medicine.disease_cause ,Antiviral Agents ,Virus ,Viral Proteins ,Cell Line, Tumor ,Drug Resistance, Viral ,medicine ,Humans ,HIV Protease Inhibitor ,Pharmacology (medical) ,Protease inhibitor (pharmacology) ,Pharmacology ,Sulfonamides ,Mutation ,Molecular Structure ,virus diseases ,HIV Protease Inhibitors ,Resistance mutation ,biology.organism_classification ,Virology ,Reverse transcriptase ,Integrase ,Phenotype ,Infectious Diseases ,Immunology ,Lentivirus ,HIV-1 ,biology.protein ,Carbamates - Abstract
At the end of 2005, an estimated 38.6 million people worldwide were living with human immunodeficiency virus (HIV), with approximately 4.1 million cases of new infections and 2.8 million deaths due to AIDS (32). Highly active antiretroviral therapy (HAART) has resulted in durable virological suppression and a marked decrease in morbidity and mortality associated with HIV, bearing testimony to the success of HAART (17, 31, 33) in Western countries, in which access to therapeutic drugs is guaranteed. However, the development of viral resistance is a major cause of treatment failure (2, 12, 21, 31, 34). Mutated, drug-resistant HIV type 1 (HIV-1) strains emerge through the combined effects of the lack of proofreading activity of the viral reverse transcriptase (RT), recombination between coinfecting isolates (3, 27), and the high replication rate of HIV in vivo (9, 35). Drug-resistant HIV is a major clinical problem, not only for patients for whom therapy fails, but for drug-naive patients, as well. In North America and Europe, it is estimated that approximately 10% of new HIV infections harbor drug-resistant mutations (15, 25, 37). Thus, novel therapeutic drugs with activity against resistant strains are needed. Other barriers to effective treatment are the toxicity of the drugs taken daily for the rest of a patient's life and the correlated lack of adherence to treatment. Therefore, new compounds should be highly specific, potent, and sufficiently bioavailable to limit the pill burden, in addition to being nontoxic. HIV-1 protease (PR) has been recognized as a therapeutic target since the approval of the first PR inhibitor (PI) in 1995. Inhibition of this 99-amino-acid homodimeric enzyme prevents the proteolytic processing of the Gag and Gag-Pol viral polyproteins into the structural proteins (p17, p24, p2, p7, p1, and p6) and the viral enzymes (PR, RT, and integrase), thereby blocking viral infectivity (14). Hence, PIs have become cornerstones in the treatment of AIDS as components of HAART both for first-line medications in treatment-naive patients and in patients with a long history of antiretroviral therapy. However, HIV can develop resistance to specific PIs through selection of amino acid substitutions in PR itself. Many mutated residues have been shown to decrease the enzyme's binding affinity for the inhibitors while the ability of PR to cleave its substrates is preserved. Distinct key or signature mutations have been associated with resistance to specific PIs (12, 18). In addition to these so-called primary mutations, other mutations, generally further away from the catalytic site, also play significant roles in resistance. However, the exact roles of these so-called compensatory or secondary mutations is not always clearly defined, although a role in enzymatic and viral fitness has been demonstrated for some of them. Moreover, some mutations in PR confer cross-resistance among multiple PIs. Often, drug selective pressure may drive the accumulation of several primary mutations against a background of particular secondary mutations to favor the emergence of cross-resistance (12). This mainly involves amino acid substitutions in PR at positions 10, 32, 46, 54, 82, 84, and 90 (8, 12). Thus, a priority in antiretroviral-drug research is now the development of new HIV inhibitors that exhibit distinct resistance profiles to provide patients with alternatives in combination therapy. To tackle this challenge, a drug discovery program was established that integrated viral resistance directly into the screening process (26, 28-30). We present the biochemical and virological characterization of a new PI, termed PL-100, that emerged from this program. PL-100 is a novel, specific, and noncytotoxic inhibitor of the HIV-1 PR that shows good antiviral activity against both wild-type laboratory strains and a wide spectrum of PI-resistant isolates.
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- 2007
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140. Review: Immunologic Response to Protease Inhibitor-Based Highly Active Antiretroviral Therapy: A Review
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Mark A. Wainberg and Bonaventura Clotet
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Adult ,business.industry ,Public Health, Environmental and Occupational Health ,HIV ,virus diseases ,Virology ,Antiretroviral therapy ,CD4 Lymphocyte Count ,Infectious Diseases ,Antiretroviral Therapy, Highly Active ,Immunology ,Humans ,RNA, Viral ,Medicine ,Protease inhibitor (pharmacology) ,Cd4 cell count ,business ,Randomized Controlled Trials as Topic ,Hiv disease - Abstract
A substantial body of evidence indicates that CD4 cell count is an important independent prognostic indicator for progression of HIV disease. Consequently, in addition to plasma HIV RNA levels, CD4 cell count change is considered to be a key surrogate marker for disease progression in clinical practice and in clinical studies. Given the relationship between changes in CD4 count and disease progression, it is notable that protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) can rapidly increase CD4 cell count early in treatment in both therapy-naïve and -experienced patients, and can sustain clinically relevant levels beyond 24 weeks. A number of trials with a follow-up of more than 3 years allow us to conclude that the gains in CD4 counts are maintained in a durable manner. This review evaluated randomized studies of PI-based and PI-boosted HAART (published between January 1996 and February 2006) to determine the effect of PI-based therapy on CD4 cell count. Only studies that assessed CD4 response in the overall patient population were included. Four mechanisms have been proposed to account for the rapid increase in CD4 cell count that occurs with HAART: CD4 cell redistribution from lymphatic tissues, increased CD4 cell production, reduction of apoptotic CD4 cells and the recovery of hematopoietic activity in bone marrow. Further research is required to clarify the relative importance of these mechanisms and ways in which they might be enhanced.
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- 2007
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141. Strategies for the optimal sequencing of antiretroviral drugs toward overcoming and preventing drug resistance
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Bluma G. Brenner, Mark A. Wainberg, and Jorge L. Martinez-Cajas
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Pharmacology ,Drug ,media_common.quotation_subject ,Stavudine ,virus diseases ,Salvage therapy ,Drug resistance ,Biology ,Emtricitabine ,Virology ,Zidovudine ,Discovery and development of non-nucleoside reverse-transcriptase inhibitors ,Infectious Diseases ,Abacavir ,Drug Discovery ,medicine ,Pharmacology (medical) ,media_common ,medicine.drug - Abstract
Drug regimens now offer more potent, less toxic and more durable choices in the treatment of HIV disease than ever before. This has led to a need to consider the convenient, sequential use of active antiretroviral combinations. Ritonavir-boosted protease inhibitors (PIs) can now be potentially sequenced in a manner that uses the least cross-resistance-prone PI at the start of therapy while leaving the most cross-resistance-prone drug for later, if the latter retains activity against commonly observed drug-resistant forms. Similarly, such new drugs as tenofovir, abacavir and emtricitabine, which make up current nucleoside backbone options, can be potentially sequenced, since each of them selects for an individual pattern of resistance mutations that are generally distinct from those selected by previously popular thymidine analogs such as zidovudine and stavudine.
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- 2007
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142. Arginine Methylation of the Human Immunodeficiency Virus Type 1 Tat Protein by PRMT6 Negatively Affects Tat Interactions with both Cyclin T1 and the Tat Transactivation Region
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Mark A. Wainberg, Baode Xie, Stéphane Richard, and Cédric F. Invernizzi
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Chloramphenicol O-Acetyltransferase ,Transcriptional Activation ,Protein-Arginine N-Methyltransferases ,Cellular immunity ,Methyltransferase ,Cyclin T1 ,Transcription, Genetic ,Arginine ,Immunology ,Biology ,Virus Replication ,Methylation ,Microbiology ,Cell Line ,Transactivation ,Genes, Reporter ,Cyclins ,Virology ,Gene expression ,Humans ,Gene Silencing ,Nuclear protein ,Luciferases ,Cyclin T ,Nuclear Proteins ,Molecular biology ,Virus-Cell Interactions ,Insect Science ,Gene Products, tat ,HIV-1 ,RNA, Viral ,tat Gene Products, Human Immunodeficiency Virus ,Protein Binding - Abstract
Arginine methylation has been shown to regulate signal transduction, protein subcellular localization, gene transcription, and protein-protein interactions that ultimately alter gene expression. Although the role of cellular protein arginine methyltransferases (PRMT) in viral gene expression is largely unknown, we recently showed that the Tat protein of human immunodeficiency virus type 1 (HIV-1) is a substrate for one such enzyme, termed PRMT6. However, the mechanism by which arginine methylation impairs the transactivation potential of Tat and the sites of arginine methylation within Tat remain obscure. We now show that Tat is a specific in vitro and in vivo substrate of PRMT6 which targets the Tat R52 and R53 residues for arginine methylation. Such Tat methylation led to decreased interaction with the Tat transactivation region (TAR) of viral RNA. Furthermore, arginine methylation of Tat negatively affected Tat-TAR-cyclin T1 ternary complex formation and diminished cyclin T1-dependent Tat transcriptional activation. Overexpression of wild-type PRMT6, but not a methylase-inactive PRMT6 mutant, reduced levels of Tat transactivation of HIV-1 long terminal repeat chloramphenicol acetyltransferase and luciferase reporter plasmids in a dose-dependent manner. In cell-based assays, knockdown of PRMT6 resulted in increased HIV-1 production and faster viral replication. Thus, PRMT6 can compromise Tat transcriptional activation and may represent a form of innate cellular immunity in regard to HIV-1 replication. Finding a way of inhibiting or stimulating PRMT6 activity might help to drive quiescently infected cells out of latency or combat HIV-1 replication, respectively.
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- 2007
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143. Kinetics of Inhibition of HIV Type 1 Reverse Transcriptase-Bearing NRTI-associated Mutations by Apricitabine Triphosphate
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Mark A. Wainberg, Hongtao Xu, Dimitrios Coutsinos, and Fernando A. Frankel
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0301 basic medicine ,Apricitabine ,Molecular Sequence Data ,030106 microbiology ,Biology ,medicine.disease_cause ,Deoxycytidine ,01 natural sciences ,03 medical and health sciences ,medicine ,Amino Acid Sequence ,Mutation ,Reverse-transcriptase inhibitor ,General Medicine ,Resistance mutation ,Nucleotidyltransferase ,Virology ,Molecular biology ,HIV Reverse Transcriptase ,Reverse transcriptase ,0104 chemical sciences ,Kinetics ,010404 medicinal & biomolecular chemistry ,Reverse Transcriptase Inhibitors ,Primer (molecular biology) ,Nucleoside ,medicine.drug - Abstract
We wished to investigate the effects of various mutations in HIV-1 reverse transcriptase (RT) on biochemical inhibition by the active form of a novel nucleoside termed apricitabine. Accordingly, we studied the efficiency of chain-termination mediated by apricitabine triphosphate (TP) in cell-free assays that used either recombinant wild-type or mutated RTs. We also performed steady-state-kinetics and primer-unblocking assays. Subtype C RTs were also analysed. The results showed that the K65R mutation in RT caused reductions in the efficiency of chain-termination of apricitabine-TP by increasing its Ki. However, K65R did not affect rates of primer unblocking for apricitabine-TP. No significant differences were found between subtype C and subtype B RTs with regard to any of the parameters studied. Other mutations such as M184V, L74V and K103N had no effect on the efficiency of chain termination by apricitabine-TP. Thus, the mechanism of reduced susceptibility to apricitabine of viruses containing K65R in RT seems to be mediated exclusively through a reduction in binding or incorporation of apricitabine-TP. Unlike some other nucleoside analogues, increased excision of incorporated apricitabine does not seem to be a cause of resistance to apricitabine.
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- 2007
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144. Apricitabine: A Novel Deoxycytidine Analogue Nucleoside Reverse Transcriptase Inhibitor for the Treatment of Nucleoside-Resistant HIV Infection
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Richard Bethell, Pedro Cahn, Mark A. Wainberg, James Sawyer, and Susan Cox
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0301 basic medicine ,Anti-HIV Agents ,Apricitabine ,030106 microbiology ,HIV Infections ,Pharmacology ,Biology ,Emtricitabine ,Deoxycytidine ,01 natural sciences ,Nucleoside Reverse Transcriptase Inhibitor ,03 medical and health sciences ,Drug Resistance, Viral ,medicine ,Humans ,Reverse-transcriptase inhibitor ,Lamivudine ,General Medicine ,Resistance mutation ,medicine.disease ,Virology ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Mitochondrial toxicity ,Nucleoside ,medicine.drug - Abstract
Existing nucleoside reverse transcriptase inhibitors for HIV disease are limited by problems of resistance and, in some cases, long-term toxicity. Apricitabine (ATC; formerly BCH10618, SPD754 and AVX754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development. ATC retains substantial in vitro activity against HIV-1 containing many mutations associated with nucleoside reverse transcriptase inhibitor resistance, showing a less than twofold reduction in susceptibility in the presence of either up to five thymidine analogue mutations or the M184V mutation. ATC showed a low potential for cellular or mitochondrial toxicity in vitro. ATC is well absorbed orally, with a bioavailability of 65–80%. Its plasma elimination half-life (approximately 3 h), and the intracellular half-life of its triphosphate (TP) metabolite (6–7 h) support twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivudine or emtricitabine, indicating that clinical co-administration of ATC together with these agents will not be possible. The drug is renally eliminated, giving a low potential for hepatic drug interactions. In a double-blind, randomized, placebo-controlled Phase II monotherapy trial in antiretroviral-naive patients, ATC doses of 1,200 and 1,600 mg/day reduced plasma viral load levels by 1.65 and 1.58 log10HIV RNA copies/ml, respectively, after 10 days of treatment ( P
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- 2007
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145. High Rates of Forward Transmission Events after Acute/Early HIV‐1 Infection
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Bluma G. Brenner, Claudine Matte, Daniela Moisi, Michel Roger, Mark A. Wainberg, Michel Ntemgwa, Réjean Thomas, Mario Legault, Jean-Guy Baril, Hugues Charest, Julie Bruneau, Roger LeBlanc, Jean-Pierre Routy, Cécile Tremblay, and Danielle Rouleau
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education.field_of_study ,Population ,Viremia ,Drug resistance ,Disease ,Biology ,medicine.disease ,Virology ,law.invention ,Infectious Diseases ,Transmission (mechanics) ,law ,Cohort ,medicine ,Immunology and Allergy ,Seroconversion ,education ,Genotyping - Abstract
BACKGROUND A population-based phylogenetic approach was used to characterize human immunodeficiency virus (HIV)-transmission dynamics in Quebec. METHODS HIV-1 pol sequences included primary HIV infections (PHIs
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- 2007
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146. Diminished efficiency of HIV-1 reverse transcriptase containing the K65R and M184V drug resistance mutations
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Mark A. Wainberg, Cédric F Invernizzi, Maureen Oliveira, and Fernando A Frankel
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viruses ,Immunology ,DNA, Single-Stranded ,HIV Infections ,Virus Replication ,Virus ,Cell Line ,Tissue culture ,Drug Resistance, Viral ,Humans ,Immunology and Allergy ,Phosphorylation ,DNA Primers ,biology ,RNA ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Nucleotidyltransferase ,Resistance mutation ,Virology ,Molecular biology ,Reverse transcriptase ,Infectious Diseases ,DNA, Viral ,Mutation ,Lentivirus ,HIV-1 ,RNA, Viral ,Reverse Transcriptase Inhibitors ,Zidovudine ,Cell culture assays - Abstract
Objectives: To determine the underlying biochemical mechanisms responsible for the diminished viral replicative capacity associated with K65R/M184V-containing viruses. Methods: We studied the efficiency of (-)ssDNA synthesis by recombinant wild-type and mutated HIV-1 reverse transcriptases in cell-free assays. In addition, we determined susceptibility levels to nucleoside analog reverse transcriptase inhibitors (NRTIs) both in cell-free and cell culture assays. Results: We observed that the K65R/M184V mutations in reverse transcriptase caused reductions in the efficiency of initiation of (-)ssDNA synthesis by increasing pausing at positions +3 and +5 as well as diminished RNA usage. These findings were confirmed in cell culture data using MT-4 cells and cord blood mononuclear cells. Conclusions: The simultaneous presence of K65R and M184V in reverse transcriptase has a negative impact with regard to the efficiency of initiation of (-)ssDNA synthesis and RNA usage, that exceeds the effect of either mutation on its own. These mechanisms, among others, are responsible for the diminished viral replicative capacity observed in tissue culture when K65R/M184V-containing viruses are studied.
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- 2007
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147. Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase
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Peter K. Quashie, Hongtao Xu, Mark A. Wainberg, Ying-Shan Han, Said Hassounah, Maureen Oliveira, Brent Richard Stranix, and Susan P. Colby-Germinario
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0301 basic medicine ,viruses ,Gene Expression ,Dengue virus ,Viral Nonstructural Proteins ,medicine.disease_cause ,Hydroxamic Acids ,Protein Structure, Secondary ,chemistry.chemical_compound ,Aedes ,RNA polymerase ,Catalytic Domain ,Cricetinae ,Pharmacology (medical) ,Nucleotide ,Sulfones ,Chelating Agents ,chemistry.chemical_classification ,virus diseases ,Integrase ,Molecular Docking Simulation ,Infectious Diseases ,Biochemistry ,Picolines ,Oligopeptides ,Protein Binding ,Recombinant Fusion Proteins ,RNA-dependent RNA polymerase ,Biology ,Antiviral Agents ,Cell Line ,Small Molecule Libraries ,03 medical and health sciences ,medicine ,Animals ,Humans ,Histidine ,Binding site ,Pharmacology ,Binding Sites ,Dose-Response Relationship, Drug ,Epithelial Cells ,biochemical phenomena, metabolism, and nutrition ,Dengue Virus ,RNA-Dependent RNA Polymerase ,Molecular biology ,Reverse transcriptase ,Kinetics ,030104 developmental biology ,Enzyme ,chemistry ,Amino Acid Substitution ,Drug Design ,biology.protein - Abstract
The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal-ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show that 5-benzenesulfonylmethyl-3-hydroxy-4-hydroxymethyl-pyridine-2-carboxylic acid hydroxyamide (termed DMB220) inhibited the RdRp activity of DENV serotypes 1 to 4 at low micromolar 50% inhibitory concentrations (IC 50s of 5 to 6.7 μM) in an enzymatic assay. The antiviral activity of DMB220 against DENV infection was also verified in a cell-based assay and showed a 50% effective concentration (EC 50 ) of
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- 2015
148. World AIDS Day 2015
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Andrew M. L. Lever and Mark A. Wainberg
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Male ,Acquired Immunodeficiency Syndrome ,Chronic condition ,Economic growth ,education.field_of_study ,business.industry ,Population ,Developing country ,HIV Infections ,Disease ,Global Health ,medicine.disease ,Pre-exposure prophylaxis ,Editorial ,Infectious Diseases ,Acquired immunodeficiency syndrome (AIDS) ,Virology ,Immunology ,Global health ,Humans ,Medicine ,Female ,business ,education ,Viral load - Abstract
World AIDS Day is a good time to remind the world that the infection that dominated the news headlines for so much of the 1980 and 1990s but now rarely makes even the front page of International media, is still here. It is still killing more than 3000 people per day of whom more than 500 are children. Ebola has come and almost gone but all through that outbreak AIDS continued to kill many fold more than ever Ebola did. There is no argument that serious inroads have been made into both the death toll and medical and social havoc wreaked by HIV compared to those early days. Massive investment has led to a larger number of new drugs being discovered and brought to market over a 30 year period than has ever been the case for any human disease at any time. The number of new diagnoses of HIV infection and AIDS worldwide is declining year by year and we have learnt that this new approach to an infection which we cannot eradicate yet, that of making infected people less infectious, actually works. Pre exposure prophylaxis (PrEP), despite its detractors and the inbuilt problems with its use, drug sharing etc. is a truly viable component of reducing transmission and should be available to all high risk individuals including sex workers in the developing world. Recent results have even shown that drug resistance that had been much feared as a consequence of PrEP has been extremely infrequent and that a strategy termed PrEP on demand in which antiretroviral drugs (ARVs) are taken only in anticipation of and following sexual relations works as well as daily doses of ARVs, thereby reducing both drug side effects and costs. Meanwhile in the wealthier world we are confronted with an almost bewildering choice of therapeutic regimes amongst which it is possible to find something that suits virtually everyone. More remarkable still is the observation that patients with HIV not only do well, they actually may have a health advantage through the intensive management of all their other medical conditions. The CHIC study in the UK now shows that a 35 year old male newly diagnosed with HIV and a CD4 count of 200, if treated appropriately and achieving a CD4 count of 350 within a year, now has a potential lifespan to age 81 which is 3 years longer than the average for an uninfected 35 year old. HIV infection teaches us many things and it has has shown that regular follow up, equivalent to comprehensive primary care, really makes a difference—quite a message for governments and health services everywhere. World AIDS Day is thus a chance to look back and celebrate our successes in what has been arguably the most impressive medical revolution ever, where a once 100 % fatal infection can now be a chronic condition associated with a normal or even prolonged lifespan. But, as alluded to in the opening paragraph, World AIDS Day is also a time to remind people that HIV has not gone away and in many parts of the world it is still the major cause of death, albeit often in concert with its lethal partner TB. People in the West may not fear the disease as much and the associated decline in stigma is welcome, but in rural Africa the infection rages on. Antiretroviral therapy has reached a huge proportion of this population but for many the logistics of attending a centre to gain access to treatment is still a significant barrier; the inconsistency of drug supplies—often leading to a triple regime temporarily becoming a dual or even monotherapy until supplies resume, is a continual driver for the emergence of drug resistance. Access is still linked to enrolment onto drug trials in some places and in others the fragility of ongoing funding, particularly since the withdrawal of PEPFAR and the reliance on the state and other charities, means that from 1 month to the next patients with HIV infection may not know for certain whether they will have reliable supplies of the life saving drugs which not only keep them healthy but also suppress their viral load, thereby reducing overall burden by making them less infectious. 2015 then is perhaps a watershed year. With a vaccine still as remote as ever, and even if one was shown to generate significant protection this year it would still be 5 years or more before it could be rolled out, we have to find other approaches to eliminating the virus. To that end we are now seeing the start of trials of therapies designed to eradicate HIV. These are aimed at the reservoir of latently infected cells containing virus that is untouched by current drugs. Our knowledge of the causes underlying HIV latency is growing and we are realizing the heterogeneity underlying this state. There is a long way to go before the so called ‘kick and kill’ strategies are augmented by highly specific therapies designed to selectively wake up each and every latent HIV but at least we are starting. Switching on a virus that is ‘asleep’ and which relies on normal cellular silencing processes to stay that way, while not switching on cellular genes in a dangerous and unnecessary way, is never going to be easy but every journey starts with a single step. To quote Churchill ‘This is not the end, it is not even the beginning of the end, but it may be the end of the beginning’. Mark Wainberg. Andrew Lever.
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- 2015
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149. Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy
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Mark A. Wainberg and Thibault Mesplède
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medicine.medical_specialty ,business.industry ,Hiv epidemic ,Public Health, Environmental and Occupational Health ,Drug resistance ,medicine.disease ,chemistry.chemical_compound ,Infectious Diseases ,First line therapy ,Viewpoint ,chemistry ,Acquired immunodeficiency syndrome (AIDS) ,Family medicine ,Dolutegravir ,Medicine ,business - Abstract
No abstract available. (Published: 4 December 2015) Citation: Wainberg MA and Mesplede T. Journal of the International AIDS Society 2015, 18 :20824 http://www.jiasociety.org/index.php/jias/article/view/20824 | http://dx.doi.org/10.7448/IAS.18.1.20824
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- 2015
150. The Combination of the R263K and T66I Resistance Substitutions in HIV-1 Integrase Is Incompatible with High-Level Viral Replication and the Development of High-Level Drug Resistance
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Maureen Oliveira, Thibault Mesplède, Mark A. Wainberg, Kaitlin Anstett, and Jiaming Liang
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Pyridones ,Immunology ,Integrase inhibitor ,Context (language use) ,HIV Infections ,Drug resistance ,HIV Integrase ,Biology ,Quinolones ,Virus Replication ,Microbiology ,Piperazines ,Raltegravir Potassium ,chemistry.chemical_compound ,Virology ,Cell Line, Tumor ,Vaccines and Antiviral Agents ,Drug Resistance, Viral ,Oxazines ,medicine ,Humans ,HIV Integrase Inhibitors ,Genetics ,Elvitegravir ,Raltegravir ,Integrase ,HEK293 Cells ,chemistry ,Amino Acid Substitution ,Insect Science ,Dolutegravir ,biology.protein ,HIV-1 ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
The R263K substitution in integrase has been selected in tissue culture with dolutegravir (DTG) and has been reported for several treatment-experienced individuals receiving DTG as part of salvage therapy. The R263K substitution seems to be incompatible with the presence of common resistance mutations associated with raltegravir (RAL), a different integrase strand transfer inhibitor (INSTI). T66I is a substitution that is common in individuals who have developed resistance against a different INSTI termed elvitegravir (EVG), but it is not known whether these two mutations might be compatible in the context of resistance against DTG or what impact the combination of these substitutions might have on resistance against INSTIs. E138K is a common secondary substitution observed with various primary resistance substitutions in RAL- and EVG-treated individuals. Viral infectivity, replicative capacity, and resistance against INSTIs were measured in cell-based assays. Strand transfer and 3′ processing activities were measured biochemically. The combination of the R263K and T66I substitutions decreased HIV-1 infectivity, replicative capacity, and strand transfer activity. The addition of the E138K substitution partially compensated for these deficits and resulted in high levels of resistance against EVG but not against DTG or RAL. These findings suggest that the presence of the T66I substitution will not compromise the activity of DTG and may also help to prevent the additional generation of the R263K mutation. Our observations support the use of DTG in second-line therapy for individuals who experience treatment failure with EVG due to the T66I substitution.IMPORTANCEThe integrase strand transfer inhibitors (INSTIs) elvitegravir and dolutegravir are newly developed inhibitors against human immunodeficiency virus type 1 (HIV-1). HIV drug-resistant mutations in integrase that can arise in individuals treated with elvitegravir commonly include the T66I substitution, whereas R263K is a signature resistance substitution against dolutegravir. In order to determine how different combinations of integrase resistance mutations can influence the outcome of therapy, we report here the effects of the T66I, E138K, and R263K substitutions, alone and in combination, on viral replicative capacity and resistance to integrase inhibitors. Our results show that the addition of R263K to the T66I substitution diminishes viral replicative capacity and strand transfer activity while not compromising susceptibility to dolutegravir. This supports the use of dolutegravir in second-line therapy for patients failing elvitegravir therapy who harbor the T66I resistance substitution.
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- 2015
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