A5045766366- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- HIV/AIDS Research and Interventions
- interferon and immune responses
- Hepatitis C virus research
- Pneumocystis jirovecii pneumonia detection and treatment
- Immune Cell Function and Interaction
- HIV-related health complications and treatments
- Cytomegalovirus and herpesvirus research
- NF-κB Signaling Pathways
- Cytokine Signaling Pathways and Interactions
- Mosquito-borne diseases and control
- Immune Response and Inflammation
- RNA regulation and disease
- HIV, Drug Use, Sexual Risk
- HIV/AIDS Impact and Responses
- Sirtuins and Resveratrol in Medicine
- Insect symbiosis and bacterial influences
- Viral Infections and Vectors
- Biological Activity of Diterpenoids and Biflavonoids
- Antimicrobial Peptides and Activities
- Nuclear Receptors and Signaling
- Drug-Induced Ocular Toxicity
- Insect Resistance and Genetics
Erasmus MC
2022-2025
Erasmus University Rotterdam
2023-2024
Jewish General Hospital
2013-2023
McGill University
2013-2023
McGill University Health Centre
2013-2020
Fundación Juan March
2016
AIDS United
2015
Manitoba Beekeepers' Association
2014
Universidad de Congreso
2013
Montreal Clinical Research Institute
2011
ABSTRACT Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase irreversibly link reverse-transcribed viral DNA host genome. INSTIs proven their high efficiency in inhibiting replication vitro and patients. However, first-generation only a modest genetic barrier resistance, allowing virus escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), reported higher...
The primary role of the innate immune response is to limit spread infectious pathogens, with activation Toll-like receptor (TLR) and RIG-like (RLR) pathways resulting in a pro-inflammatory required combat infection. Limiting these signaling likewise essential prevent tissue injury host. Triad3A an E3 ubiquitin ligase that interacts several components TLR modulates activity. In present study, we demonstrate negatively regulates RIG-I RNA sensing pathway through Lys48-linked,...
Abstract Background Clinical studies have shown that integrase strand transfer inhibitors can be used to treat HIV-1 infection. Although the first-generation are susceptible emergence of resistance mutations impair their efficacy in therapy, such has not been identified date drug-naïve patients who treated with second-generation inhibitor dolutegravir. During previous vitro selection study, we a R263K mutation as most common substitution arise presence dolutegravir H51Y arising secondary...
Integrase strand transfer inhibitors (INSTIs) are recommended for first-line HIV therapy based on their relatively high genetic barrier to resistance. Although raltegravir (RAL) and elvitegravir (EVG) resistance profiles well-characterized, patterns dolutegravir (DTG), bictegravir (BIC), cabotegravir (CAB) remain largely unknown. Here, in vitro drug selections compared the development of DTG, BIC, CAB, EVG RAL using clinical isolates from treatment-naïve primary infection (PHI) cohort...
ABSTRACT Human papillomaviruses (HPVs) are the etiological agents of cervical cancer and other human malignancies. HPVs classified into high- low-risk genotypes according to their association with cancer. Host cell transformation by high-risk relies in part on ability viral E6 protein induce degradation p53. We report development a cellular assay that accurately quantifies p53 activity vivo , based fusion Renilla luciferase (RLuc-p53). This was used measure activities proteins from 29...
First-generation integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL) and elvitegravir (EVG), have been clinically proven to be effective antiretrovirals for the treatment of HIV-positive patients. However, their relatively low genetic barrier resistance makes them susceptible emergence drug mutations. In contrast, dolutegravir (DTG) is a newer INSTI that appears high in vivo. mutation R263K followed by polymorphic substitution M50I has observed cell culture. The...
A high genetic barrier to resistance the integrase strand transfer inhibitor (INSTI) dolutegravir has been reported in vitro and vivo. We describe dynamics of INSTI resistance-associated mutations (INSTI-RAMs) 3'-polypurine tract (3'-PPT) relation virologic failure (VF) observed randomized Dolutegravir as Maintenance Monotherapy for HIV-1 study (DOMONO, NCT02401828).From 10 patients with VF, plasma samples were collected before start cART during used generate Sanger sequences integrase, 5'...
Dolutegravir (DTG) is the latest antiretroviral (ARV) approved for treatment of human immunodeficiency virus (HIV) infection. The G118R substitution, previously identified with MK-2048 and raltegravir, may represent initial substitution in a dolutegravir resistance pathway. We have found that subtype C integrase proteins low enzymatic cost associated mostly at strand transfer step integration, compared to either B or recombinant CRF02_AG proteins. Subtype circulating form AG (CRF02_AG)...
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 the G118R mutation arose following switch from elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine dolutegravir monotherapy. The also in treatment-experienced patient switched genetic basis for selection and potential phenotypic outcome was ascertained. Genotypic analysis performed on patients virological...
Drug resistance mutations (DRMs) have been reported for all currently approved anti-HIV drugs, including the latest integrase strand transfer inhibitors (INSTIs). We previously used new INSTI dolutegravir (DTG) to select a G118R substitution in tissue culture and also showed that secondary substitutions emerged at positions H51Y E138K. Now, we characterized impact of substitution, alone or combination with either E138K, on 3' processing activity. The results show primarily impacted step...
Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that methylates residues on histones and transcription factors. In addition, PRMT6 inhibits HIV-1 replication in cell culture by directly methylating interfering with the functions of several proteins, i.e. Tat, Rev nucleocapsid (NC). also displays automethylation capacity but role this post-translational modification its antiretroviral activity remains unknown.Here we report identification liquid chromatography-mass...
ABSTRACT HIV-1 can be transmitted as cell-free virus or via cell-to-cell contacts. Cell-to-cell transmission between CD4 + T cells is the more efficient mode of and predominant in lymphoid tissue, where majority resides. Yet cellular mechanisms underlying productive uninfected target are unclear. Although it has been demonstrated that take up endocytosis, definitive links this process infection remain undefined, route proposed to nonproductive. Here, we report occur endocytosis a...
Objective: Among 1222 antiretroviral-naive patients who received dolutegravir (DTG) as part of first-line therapy, none has developed resistance against this compound after 48–96 weeks follow-up. Moreover, only four occurrences virological failure with mutations have been documented in previously drug-experienced DTG a first time integrase inhibitor component second-line regimen. The R263K mutation was observed two these individuals suboptimal background regimens. We selected at position...
Human immunodeficiency virus (HIV) treatment with antiretroviral regimens containing integrase strand transfer inhibitors such as dolutegravir (DTG) and bictegravir (BIC) offers high levels of protection against the development drug resistance mutations. Despite this, to DTG BIC can occur through R263K substitution.
The immunoregulatory transcriptional modulators - IFN-regulatory factor (IRF)-3 and IRF-7 possess similar structural features but distinct gene-regulatory potentials. For example, adenovirus-mediated transduction of the constitutively active form IRF-3 triggered cell death in primary human MPhi, whereas expression induced a strong anti-tumoral activity vitro. To further characterize target genes involved these cellular responses, profiles IRF-3- or IRF-7-transduced MPhi were compared used to...
BackgroundThe results of several clinical trials suggest that the integrase inhibitor dolutegravir may be less prone than other drugs to emergence HIV drug resistance mutations in treatment-naive patients. We have shown R263K mutation commonly emerged during tissue culture selection studies with and conferred low levels this while simultaneously diminishing both replication capacity enzymatic activity. E138K has been identified as a secondary for also observed clinic inhibitors raltegravir...
Zika virus (ZIKV) outbreak has emerged as a global health threat, particularly in tropical areas, over the past few years. No antiviral therapy or vaccine is available at present. For these reasons, repurposing clinically approved drugs against ZIKV infection may provide rapid and cost‐effective benefits. Here, we explored this strategy screened eight FDA‐approved for activity using cell‐based assay. Our results show that antimalarial drug amodiaquine anti‐ZIKV with EC 50 low micromolar...
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 the most for INSTI dolutegravir, an treatment-experienced individual recently failed dolutegravir-based therapy, being only resistance-associated change reported. Given that different pathways can sometimes synergize confer high levels of antiretroviral drugs, we studied effects association R263K. Because Glu157...