A5057060792- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- HIV/AIDS Research and Interventions
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Lymphoma Diagnosis and Treatment
- T-cell and B-cell Immunology
- Cytomegalovirus and herpesvirus research
- SARS-CoV-2 detection and testing
- Immunotherapy and Immune Responses
- Respiratory viral infections research
- Biosensors and Analytical Detection
- Hepatitis C virus research
- T-cell and Retrovirus Studies
- Genomics and Phylogenetic Studies
- Blood groups and transfusion
- Reproductive System and Pregnancy
- HIV, Drug Use, Sexual Risk
- vaccines and immunoinformatics approaches
- Hepatitis B Virus Studies
- Biochemical and Molecular Research
- Pregnancy and preeclampsia studies
- Streptococcal Infections and Treatments
- Global Maternal and Child Health
- Herpesvirus Infections and Treatments
Simon Fraser University
2015-2025
AIDS Vancouver
2018-2024
Holy Family Hospital
2022
Pakistan Institute of Medical Sciences
2021
Aga Khan University
2011-2013
Aga Khan University
2011-2013
Abstract The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two regions distinguish genomically proviruses against large background of defective ones, and its application has yielded insights into persistence. Reports failures however, attributed polymorphism, have recently emerged. Here, we describe diverse North American cohort people with...
Characterizing the genetically diverse HIV sequences that persist in reservoir despite antiretroviral therapy (ART) is critical to cure efforts. Our observations confirm proviruses persisting blood on ART, which are largely defective, broadly reflect extent of within-host evolution pre-ART. Moreover, on-ART clonal expansion not appreciably accompanied by loss distinct proviral lineages. In fact, genetic composition remained stable all but one participant, whom, after 12 years dating around...
HIV persists in tissues during antiretroviral therapy (ART), but the relative contribution of different anatomical compartments to viral reservoir humans remains unknown. We performed an extensive characterization reservoirs two men who donated their bodies cure research and had been on suppressive ART for years. DNA is detected all tissues, with large variations across between participants. Intact genomes represent 2% 25% proviruses participants are mainly secondary lymphoid organs, spleen...
HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as epidemic progresses. To assess extent and phenotypic impact of this phenomenon in an immunogenetically diverse we genotypically functionally compared linked HLA (Gag/Nef) sequences from 358 historic (1979–1989) 382 modern (2000–2011) specimens four key cities North American (New York, Boston, San Francisco,...
Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance approved raltegravir (RAL) elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for phenotype a panel containing with additional accessory substitutions. accumulation multiple confers all 5 inhibitors....
Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in controllers during chronic phase, but kinetics mechanisms of attenuation such individuals remain unclear. We examined plasma RNA-derived clones from 10 recently infected who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) 50 did not control progressors). acute displayed a lesser ability downregulate CD4 HLA class I cell...
Abstract Nasopharyngeal swabs are critical to the diagnosis of respiratory infections including coronavirus disease 2019, but collection techniques vary. We compared 2 recommended nasopharyngeal swab in adult volunteers and found that rotation following contact did not recover additional nucleic acid (as measured by human DNA/RNA copy number). Rotation was also less tolerable for participants. Notably, both discomfort recovery were significantly higher Asian participants, consistent with...
The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, primarily CD4+ T cells, is main barrier to developing an effective cure. Our understanding genetics and dynamics persisting within distinct cell subsets, however, remains incomplete. Using single-genome amplification, we characterized subgenomic proviral sequences (nef region) from naive, central memory, transitional effector memory cells five HIV-infected individuals on long-term combination...
A fundamental challenge in the era of next-generation sequencing (NGS) is to design effective treatments tailored mutational profiles tumors. Many newly discovered cancer mutations are difficult target pharmacologically; however, T-cell-based therapies may provide a valuable alternative owing exquisite sensitivity and specificity antigen recognition. To explore this concept, we assessed immunogenicity panel genes that common sites driver follicular lymphoma, an immunologically sensitive yet...
The emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibits in vitro replication HIV-1, including resistant licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24(Gag) production was unaffected, but virion...
The greatest HIV-1 genetic diversity is found in West/Central Africa due to the pandemic’s origins this region, but remains understudied. We characterized subtype (from both sub-genomic and full-genome viral sequences), drug resistance coreceptor usage 103 predominantly (90%) antiretroviral-naive individuals living with Ghana. Full-genome subtyping confirmed circulating recombinant form CRF02_AG as dominant (53.9%) complex 06_cpx (4%) present well. Unique recombinants, most of which were...
HLA-B*13 is associated with superior in vivo HIV-1 viremia control. Protection thought to be mediated by sustained targeting of key cytotoxic T lymphocyte (CTL) epitopes and viral fitness costs CTL escape Gag although additional factors may contribute. We assessed the impact 10 published B*13-associated polymorphisms Gag, Pol, Nef, 23 biologically relevant combinations, on replication capacity Nef-mediated reduction cell surface CD4 HLA class I expression. Mutations were engineered into...
Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding burden, genetic diversity, and longevity persisting in diverse individuals with is critical to this goal, but these characteristics remain understudied some groups. Among them are viremic controllers-individuals who naturally suppress low levels for whom nevertheless recommended. We reconstructed within-host evolutionary histories...
ABSTRACT In order to cure human immunodeficiency virus (HIV), we need better understand the within-host evolutionary origins of small reservoir genome-intact proviruses that persist within infected cells during antiretroviral therapy (ART). Most prior studies on dynamics, however, did not discriminate from vast background defective ones. We reconstructed pre-ART HIV histories in six individuals and leveraged this information infer ages intact sampled after an average >9 years ART, along...
The current study was conducted to explore the origins of HIV epidemics among Afghan refugees in Pakistan and native Afghans Afghanistan. Phylogenetic analysis gag gene from 40 samples showed diverse variants, originating a number countries. Intermixing variants may give rise seeding infections with rare strains which pose serious challenges for treatment control infection.
Routine HIV drug resistance genotyping identified an integrase sequence harbouring T97A, E138K, G140S and Q148H, with high predicted to all strand transfer inhibitors (INSTIs).To assess the impact of these substitutions alone together on phenotypic INSTI susceptibility.We constructed recombinant NL4.3 viruses mutation combinations in autologous sequence. Viruses were grown GFP-reporter CD4+ T-cells presence 0.01-1000 nM raltegravir, elvitegravir, dolutegravir, bictegravir, cabotegravir....
Pediatric human immunodeficiency virus (HIV) care in resource-limited settings remains a major challenge to achieving global HIV treatment and virologic suppression targets, part because the administration of combination antiretroviral therapies (cART) is inherently complex this population viral load drug resistance genotyping are not routinely available these settings. Children may also be at elevated risk transmission drug-resistant as result suboptimal for prevention mother-to-child...
The lung is an understudied site of HIV persistence. We isolated 898 subgenomic proviral sequences ( nef ) by single-genome approaches from blood and nine individuals on long-term suppressive antiretroviral therapy (ART), characterized genetic diversity compartmentalization using formal tests. Consistent with clonal expansion as a driver persistence, identical comprised between 8% to 86% within-host datasets, though their location (blood vs. lung) followed no consistent pattern. majority...
Abstract Hypermutated proviruses, which arise in a single Human Immunodeficiency Virus (HIV) replication cycle when host antiviral APOBEC3 proteins introduce extensive guanine to adenine mutations throughout the viral genome, persist all people living with HIV receiving antiretroviral therapy (ART). However, hypermutated sequences are routinely excluded from phylogenetic trees because their complicate inference, and as result, we know relatively little about within-host evolutionary origins...