<b>Copyright information:</b>Taken from "Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury"Critical Care 2003;7(6):R176-R183.Published online 10 Oct... more
<b>Copyright information:</b>Taken from "Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury"Critical Care 2003;7(6):R176-R183.Published online 10 Oct 2003PMCID:PMC374373.Copyright © 2003 Davani et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Hearts were prepared for Langendorf reperfusion and perfused until the monitored heart rate and pressure were stable (approximately 3–5 min); then they were subjected to 20 min of ischemia followed by reperfusion. Perfusate solution was collected (approximately 1 ml/4 min) around each time point for determination of CPK activity. For all time points, tumour necrosis factor (TNF)-α reperfusion generated a significant elevation in the detectable amount of CPK activity relative to that detected with insulin-like growth factor (IGF)-1 reperfusion (&lt; 0.005, by analysis of variance).
Additional file 2: Codon-by-codon analysis of Nef sequence with function.
Insulin-like growth factor-1 protects ischemic murine
IntroductionMost existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform... more
IntroductionMost existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH.Methods and analysisThis multicentred observational Canadian cohort study will enrol 400 PLWH aged>16 years from Montreal, Ottawa, Toronto and Vancouver. Subpopulations of PLWH of interest will include individuals: (1) >55 years of age; (2) with CD4 counts <350 cells/mm3; (3) with multimorbidity (>2 comorbidities) and (4) ‘stable’ or ‘reference’ PLWH (CD4 T cells >350 cells/mm3, suppressed viral load for>6 months and<1 comorbidity). Data for 1000 HIV-negative controls will be obtained via a parallel cohort study (Stop the Spread Ottawa), using similar time points and methods. Participants receiving>1 COVID-19 vaccine will attend five visits: prevaccination; 1 month following the first vaccine dose; and ...
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Research Interests: Immunology, Biology, Virology, Medicine, T cell receptor, and 8 moreHIV, Humans, CD, Perforin, Antigen, Human leukocyte antigen, epitope, and HIV infections
Research Interests: Infectious Diseases, Medicine, HIV, Multivariate Analysis, Biological Sciences, and 15 moreAntiretroviral Therapy, Humans, Internal Medicine, Mutation, HIV protease, HIV drug resistance, Drug Resistance, Patient Compliance, Incidence, British Columbia, Infectious, Adult, Highly Active Antiretroviral Therapy, Medical and Health Sciences, and HIV infections
Insulin-like growth factor (IGF)-1 is a well characterized growth factor that plays a role in the regulation of myocardial structure and function. Using an ex vivo murine model, Davani and coworkers, in this issue of Critical Care,... more
Insulin-like growth factor (IGF)-1 is a well characterized growth factor that plays a role in the regulation of myocardial structure and function. Using an ex vivo murine model, Davani and coworkers, in this issue of Critical Care, demonstrate that IGF-1 confers cardiac protection against ischemia via mitochondria-dependent mechanisms. Those investigators used the ratio of mitochondrial to nuclear DNA to demonstrate that IGF-1, which prevents reduction in this ratio during reperfusion, provides cytoprotection. This commentary also reviews mechanisms of IGF-1 function and provides a graphic representation of IGF-1 signaling mechanisms in potential crosstalk relations with mediators of inflammation in the heart (specifically tumor necrosis factor-alpha).
Research Interests: Medicine, Critical Care, Signal Transduction, Mitochondrial DNA, Humans, and 13 moreMice, Animals, Cytoprotection, nuclear DNA, Crosstalk, Tumor necrosis factor-alpha, Reperfusion injury, Growth Factor, Murine Model, Cell Survival, Insulin Like Growth Factor, Tumor necrosis factor, and Medical and Health Sciences
The greatest HIV-1 genetic diversity is found in West/Central Africa due to the pandemic’s origins in this region, but this diversity remains understudied. We characterized HIV-1 subtype diversity (from both sub-genomic and full-genome... more
The greatest HIV-1 genetic diversity is found in West/Central Africa due to the pandemic’s origins in this region, but this diversity remains understudied. We characterized HIV-1 subtype diversity (from both sub-genomic and full-genome viral sequences), drug resistance and coreceptor usage in 103 predominantly (90%) antiretroviral-naive individuals living with HIV-1 in Ghana. Full-genome HIV-1 subtyping confirmed the circulating recombinant form CRF02_AG as the dominant (53.9%) subtype in the region, with the complex recombinant 06_cpx (4%) present as well. Unique recombinants, most of which were mosaics containing CRF02_AG and/or 06_cpx, made up 37% of sequences, while “pure” subtypes were rare (<6%). Pretreatment resistance to at least one drug class was observed in 17% of the cohort, with NNRTI resistance being the most common (12%) and INSTI resistance being relatively rare (2%). CXCR4-using HIV-1 sequences were identified in 23% of participants. Overall, our findings advance...
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ABSTRACTBackgroundLimited data exist regarding longer-term antibody responses following three-dose COVID-19 vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people living with HIV (PLWH) receiving... more
ABSTRACTBackgroundLimited data exist regarding longer-term antibody responses following three-dose COVID-19 vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-(WT), Omicron BA.1- and Omicron BA.5-specific responses up to six months post-third dose in 64 PLWH and 117 controls who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time.DesignLongitudinal observational cohort.MethodsWe quantified WT- and Omicron-specific Anti-Spike receptor-binding domain IgG concentrations, ACE2 displacement activities and live virus neutralization at one, three and six months post-third vaccine dose.ResultsThird doses boosted all antibody measures above two-dose levels, but BA.1-specific responses remained significantly lower than WT-specific ones, with BA.5-specific responses lower still. Serum IgG concentrations declined at similar ...
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<p>A minimum of ≥50,000 reconstructions of the ancestral sequence at the root of the Gag and Nef phylogenies were performed, and the inferred MRCA was computed as the “grand consensus” of these replicate reconstructions. For each... more
<p>A minimum of ≥50,000 reconstructions of the ancestral sequence at the root of the Gag and Nef phylogenies were performed, and the inferred MRCA was computed as the “grand consensus” of these replicate reconstructions. For each codon, reconstruction confidence (computed as the frequency of each amino acid observed across all reconstructions) is indicated on the y-axis on a scale from 0 (0%) to 1 (100%). Blue letters represent the highest-confidence residue at each position; green letters represent lower-confidence residues. All amino acids observed at >0.01 (>1%) reconstruction frequency are shown. Yellow boxes highlight positions where the highest-confidence (blue) inferred ancestral residue differs from the North American consensus B sequence (displayed in <b><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004295#pgen.1004295.s003" target="_blank">Figure S3</a></b>).</p
Research Interests: Evolutionary Biology, Genetics, Microbiology, Epidemiology, Immunology, and 15 moreImmune response, Computational Biology, Medical Microbiology, Cell Biology, HIV, Biological Sciences, American, Microbial Evolution, Immune system, HIV epidemiology, Host Pathogen Interactions, Microbial Pathogens, Blood cells, ANCESTRAL, and GAG
The lung is an understudied site of HIV persistence. We isolated 882 subgenomic proviral sequences by single-genome approaches from blood and lung from nine individuals on long-term suppressive antiretroviral therapy (ART), and... more
The lung is an understudied site of HIV persistence. We isolated 882 subgenomic proviral sequences by single-genome approaches from blood and lung from nine individuals on long-term suppressive antiretroviral therapy (ART), and characterized genetic diversity and compartmentalization using formal tests. Consistent with clonal expansion as a driver of HIV persistence, identical sequences comprised between 9% to 86% of within-host datasets, though their location (blood vs. lung) followed no consistent pattern. The majority (77%) of participants harbored at least one sequence shared across blood and lung, supporting the migration of clonally-expanded cells between sites. No participant exhibited genetic compartmentalization so obvious that it was visually apparent in a phylogeny. When formal tests were applied however, two (22%) participants showed modest yet significant support for compartmentalization when analysis was restricted to distinct proviruses per site. This increased to fou...
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<p><b>Panel A:</b> Differences in Shannon entropy (Δentropy) between modern and historic sequences are shown for every Gag codon. Positive y-values indicate higher entropy in modern vs. historic sequences at that codon;... more
<p><b>Panel A:</b> Differences in Shannon entropy (Δentropy) between modern and historic sequences are shown for every Gag codon. Positive y-values indicate higher entropy in modern vs. historic sequences at that codon; negative y-values indicate the opposite. Red bars indicate significant entropy differences (defined as p<0.001, q<0.01); blue colors indicate differences that do not reach this significance threshold. Grey dots designate known HIV sites under selection by HLA (as defined in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004295#pgen.1004295-Carlson1" target="_blank">[43]</a>). Green dots designate sites that display significant evidence of pervasive positive selection (dN/dS>1; posterior probability >0.9). <b>Panel B:</b> Same as panel A, but sorted by decreasing Δentropy rather than codon order. <b>Panel C:</b> Graphical depiction of a 2×2 contingency table stratifying variable (<99% conserved) Gag codons based on their status as HLA-associated (yes vs. no), and whether they exhibited significant Δentropy between modern and historic datasets (p<0.001 [red] vs. not [blue]). Ns are indicated above each bar. <b>Panel D:</b> Graphical depiction of a 2×2 contingency table stratifying variable (<99% conserved) Gag codons based on their status as HLA-associated (yes vs. no) and evidence that they are under significant pervasive positive selection (dN/dS>1; posterior probability >0.9 [green] vs. not [black]). Ns are indicated above each bar.</p
Research Interests: Evolutionary Biology, Genetics, Microbiology, Epidemiology, Immunology, and 15 moreMolecular Biology, Immune response, Computational Biology, Medical Microbiology, Cell Biology, HIV, Biological Sciences, Diversification, Microbial Evolution, Immune system, HIV epidemiology, Host Pathogen Interactions, Microbial Pathogens, Blood cells, and Exhibiting
ABSTRACTBackgroundLonger-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose.MethodsWe measured antibodies against the SARS-CoV-2... more
ABSTRACTBackgroundLonger-term humoral responses to two-dose COVID-19 vaccines remain incompletely characterized in people living with HIV (PLWH), as do initial responses to a third dose.MethodsWe measured antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement and viral neutralization against wild-type and Omicron strains up to six months following two-dose vaccination, and one month following the third dose, in 99 PLWH receiving suppressive antiretroviral therapy, and 152 controls.ResultsThough humoral responses naturally decline following two-dose vaccination, we found no evidence of lower antibody concentrations nor faster rates of antibody decline in PLWH compared to controls after accounting for sociodemographic, health and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after two doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantial...
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Thwarting HIV Multiple genome-wide association studies have revealed that human leukocyte antigen (HLA) genes of the major histocompatibility complex locus have the strongest impact on HIV. In particular, a single-nucleotide polymorphism... more
Thwarting HIV Multiple genome-wide association studies have revealed that human leukocyte antigen (HLA) genes of the major histocompatibility complex locus have the strongest impact on HIV. In particular, a single-nucleotide polymorphism 35 base pairs upstream of HLA-C shows significant association with viral load and protection against HIV. How HLA-C mediates these effects is unknown. Apps et al. (p. 87 ) now demonstrate that increasing surface expression of HLA-C is associated with reduced viral load and reduced rate of progression to low CD4 + T cell counts in African and European Americans. High HLA-C expression likely promoted improved HIV control through a more effective cytotoxic CD8 + T cell response. In contrast to HIV infection, high HLA-C expression was associated with a higher risk of the inflammatory bowel disease, Crohn's disease.
Research Interests: Immunology, Science, Biology, Medicine, Multidisciplinary, and 15 moreHIV, Humans, Mutation, African Americans, Single Nucleotide Polymorphism, Amino Acid Sequence, Allele, Crohn Disease, Gene Expression Regulation, Viral Load, Molecular Sequence Data, alleles, Human leukocyte antigen, Anti-retroviral agents, and HIV infections
Research Interests: Algorithms, Immunology, Molecular Biology, Biology, Workflow, and 15 moreMedicine, DNA, Software Design, Humans, Polymerase Chain Reaction, Optometry and Ophthalmology, Genomic DNA, Genotype, Genotyping, Reproducibility of Results, Laboratory Automation, Freezing, Exon, Reference standards, and limit of detection
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ABSTRACTSARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have documented serial Omicron infections. We characterized SARS-CoV-2 humoral responses... more
ABSTRACTSARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have documented serial Omicron infections. We characterized SARS-CoV-2 humoral responses in a healthy young person who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to those of 124 COVID-19 naive vaccinees. One month after the second and third vaccine doses, the participant’s wild-type and BA.1-specific IgG, ACE2 competition and virus neutralization activities were average for a COVID-19 naive triple-vaccinated individual. BA.1 infection boosted the participant’s responses to the cohort ≥95th percentile, but even this strong “hybrid” immunity failed to protect against BA.2. Moreover, reinfection increased BA.1 and BA.2-specific responses only modestly. Results illustrate the risk of Omicron infection in fully vaccinated individuals and high...
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Additional file 1: Nef sequences and related functional data.
ABSTRACTHumoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2... more
ABSTRACTHumoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and ∼11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any respons...
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Nasopharyngeal swabs are critical to the diagnosis of respiratory infections including COVID-19, but collection techniques vary. We compared two recommended nasopharyngeal swab collection techniques in adult volunteers and found that swab... more
Nasopharyngeal swabs are critical to the diagnosis of respiratory infections including COVID-19, but collection techniques vary. We compared two recommended nasopharyngeal swab collection techniques in adult volunteers and found that swab rotation following nasopharyngeal 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 and nucleic acid recovery were significantly higher in Asians, consistent with nasal anatomy differences. Our results suggest that it is unnecessary to rotate the swab in place following contact with the nasopharynx, and reveal that procedural discomfort levels can differ by ethnicity.summaryNasopharyngeal swabs are critical to COVID-19 diagnostics, but collection techniques vary. Comparison of two collection techniques revealed that swab rotation did not recover more nucleic acid and was more uncomfortable. Discomfort and biological material recover...
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Human leukocyte antigen class I (HLA)-restricted CD8(+) T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants... more
Human leukocyte antigen class I (HLA)-restricted CD8(+) T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4(+) T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that requi...
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Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard... more
Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast...
Research Interests: Africa, General Internal Medicine, Medicine, HIV, Molecular Epidemiology, and 15 morePhylogeny, South Africa, Humans, Mutation, Europe, Americas, Asia, Science Technology, Sub Saharan Africa, Base Sequence, Reverse Transcriptase, Treatment programs, antiretroviral treatment, Medical and Health Sciences, and HIV infections
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV... more
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integ...
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Significance Factors that influence the virulence of HIV are of direct relevance to ongoing efforts to contain, and ultimately eradicate, the HIV epidemic. We here investigate in Botswana and South Africa, countries severely affected by... more
Significance Factors that influence the virulence of HIV are of direct relevance to ongoing efforts to contain, and ultimately eradicate, the HIV epidemic. We here investigate in Botswana and South Africa, countries severely affected by HIV, the impact on HIV virulence of adaptation of HIV to protective HLA alleles such as HLA-B*57. In Botswana, where the epidemic started earlier and reached higher adult seroprevalence than in South Africa, HIV replication capacity is lower. HIV is also better adapted to HLA-B*57, which in Botswana has no protective effect, in contrast to its impact in South Africa. Modelling studies indicate that increasing antiretroviral therapy access may also contribute to accelerated declines in HIV virulence over the coming decades.
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Research Interests: Molecular Evolution, Comparative Study, HIV, Mexico, Humans, and 14 moreHIV protease, Female, Male, Hiv Infection, Molecular Phylogenetics and Evolution, Statistical Power, Clinical Sciences, MEXICO, Retrovirology, Network Model, Cohort Studies, Gene frequency, HIV infections, and Genetic background
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Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in... more
Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. g ag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia ( P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impa...
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Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness... more
Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of human leukocyte antigen (HLA) class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins of elite controllers.
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Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase gamma. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in... more
Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase gamma. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy. Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68 percent lower than those of non-HIV-infected controls and 43 percent lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P=0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels. Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy.
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Table of contents A1 Introduction to the 2nd synchronicity forum of GHRI/CHVI-funded Canadian and African HIV prevention and vaccine teams O1 Voluntary medical male circumcision for prevention of heterosexual transmission of HIV in adult... more
Table of contents A1 Introduction to the 2nd synchronicity forum of GHRI/CHVI-funded Canadian and African HIV prevention and vaccine teams O1 Voluntary medical male circumcision for prevention of heterosexual transmission of HIV in adult males in Soweto: What do indicators and incidence rate show? Hillary Mukudu, Neil Martinson, Benn Sartorius O2 Developing a peer-led community mobilization program for sex workers in Soweto: HIV risk and demographics Jenny Coetzee, Janan Dietrich, Kgaugelo Mokgatswana, Rachel Jewkes, Glenda E. Gray O3 Salient beliefs about adherence: A qualitative survey conducted as part of the demonstration study on "treatment as prevention" (TasP) and "pre-exposure prophylaxis" (PrEP) among female sex workers (FSWS) in Cotonou, Benin Marylène Dugas, Luc Béhanzin, Fernand A. Guédou, Marie-Pierre Gagnon, Michel Alary O4 Relative perception of risk as a driver of unsafe sexual practices among key populations: Cases of fisherfolk and women and the...
<b>Copyright information:</b>Taken from "Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury"Critical Care 2003;7(6):R176-R183.Published online 10 Oct... more
<b>Copyright information:</b>Taken from "Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury"Critical Care 2003;7(6):R176-R183.Published online 10 Oct 2003PMCID:PMC374373.Copyright © 2003 Davani et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. The mtDNA : nDNA ratio was determined for the following conditions: control; ischemia without reperfusion; modified Kreb's Henseleit working solution (MK) alone for 1 hour; MK alone for 2 hours; MK plus insulin-like growth factor (IGF)-1 for 1 hour; and MK with insulin-like growth factor (IGF)-1 for 2 hours. The number within each histogram represents the number of hearts processed for that condition. The values for mtDNA : nDNA ratio in the controls, ischemic myocardial tissue, and either reperfusion group (MK or IGF-1) were significantly different from each other (&lt; 0.05).
<b>Copyright information:</b>Taken from "Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury"Critical Care 2003;7(6):R176-R183.Published online 10 Oct... more
<b>Copyright information:</b>Taken from "Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury"Critical Care 2003;7(6):R176-R183.Published online 10 Oct 2003PMCID:PMC374373.Copyright © 2003 Davani et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Tracings from continuous monitor recordings obtained during ischemia and reperfusion. Each tracing demonstrates the aortic and left ventricular transduced pressure over time. The mid-point in the tracing is at 20 min of reperfusion. The conditions are modified modified Kreb's Henseleit working solution (MK) alone, MK plus tumour necrosis factor (TNF)-α, and MK plus insulin-like growth factor (IGF)-1. Determination of cardiac performance is as described in the Methods section (see text) and includes calculation of the pressure gradient between the systolic and diastolic pressure transductions from the aorta and left ventricle. As demonstrated, reperfusion with IGF-1 generates a significant improvement in cardiac performance at all time points. Analysis demonstrated a significant difference between reperfusion with IGF-1 plus MK as compared with MK alone and MK plus TNF-α (&lt; 0.005).
Understanding the dynamics of viral adaptation to genetic variations in the human host is of vital importance in the search for vaccines against highly mutagenic viruses. One particular controversy is the extent of HIV evolution... more
Understanding the dynamics of viral adaptation to genetic variations in the human host is of vital importance in the search for vaccines against highly mutagenic viruses. One particular controversy is the extent of HIV evolution attributable to Human Leukocyte Antigen (HLA) mediated selection pressure. In 2002, Moore et al. showed that correlations between the HLA alleles of the current host and HIV-1 polymorphisms indicate the presence of HLA-I selection pressure on HIV (1). We recently showed, however, that lineage effects in the virus lead to a high prevalence of spurious associations in the original study and proposed a novel Bayesian Network approach that corrects for these lineage effects (2). Unfortunately, the number of patients in that study did not yield sufficient power to answer the present question. To identify associations between a given HLA allele X and amino acid polymorphism Y, we build a maximum likelihood phylogenetic tree from viral gene sequences and use a like...
High-resolution HLA typing plays a central role in many areas of immunology, such as transplant matching, identifying immunogenetic risk factors for disease, studying how the genomes of pathogens evolve in response to immune selection... more
High-resolution HLA typing plays a central role in many areas of immunology, such as transplant matching, identifying immunogenetic risk factors for disease, studying how the genomes of pathogens evolve in response to immune selection pressures, and vaccine design. However, high-resolution HLA typing is frequently unavailable due to its high cost or the inability to re-type historical data. We recently introduced and evaluated a method for statistical, in silico refinement of ambiguous and/or low-resolution HLA data (Listgarten, et al. 2008). Here we present a summary of this work for the histocompatibility community. A tool based on our approach is available for research purposes at
Background: The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro... more
Background: The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef’s most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D. Results: Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naïve, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Co...
Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main... more
Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reservoirs begins shortly after infection, and cells containing integrated proviral DNA are extremely stable once suppressive antiretroviral therapy (ART) is initiated. During untreated HIV infection however, reservoir turnover is likely to be more dynamic. Understanding these dynamics is important because the longevity of the persisting proviral pool during untreated infection dictates reservoir composition at ART initiation. If the persisting proviral pool turns over slowly pre-ART, then HIV sequences seeded into it during early infection would have a high likelihood of persisting for long periods. However, if pre-ART turnover was rapid, the persisting proviral pool would rapidly shift towar...
HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long... more
HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure.
Research Interests: Microbiology and Mbio
ABSTRACTBackgroundmRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized.MethodsAnti-spike RBD antibody titers, ACE2... more
ABSTRACTBackgroundmRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized.MethodsAnti-spike RBD antibody titers, ACE2 competition and virus neutralizing activities were longitudinally assessed in 151 healthcare workers and older adults (overall aged 24-98 years) up to three months after vaccination.ResultsOlder adults exhibited lower antibody responses after one and two vaccine doses for all measures. In multivariable analyses correcting for sociodemographic, chronic health and vaccine-related variables, age remained independently associated with all response outcomes. The number of chronic health conditions was additionally associated with lower binding antibody responses after two doses, and male sex with lower ACE2 competition activity after one dose. Responses waned universally at three months after the second dose, but binding antibodies, ACE2 competition and...
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The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish... more
The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in ...
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ABSTRACTBackgroundSeveral Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely... more
ABSTRACTBackgroundSeveral Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19.MethodsWe assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N) and spike protein receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-Co...
False-negative severe acute respiratory syndrome coronavirus 2 test results can negatively impact the clinical and public health response to coronavirus disease 2019 (COVID-19). We used droplet digital polymerase chain reaction (ddPCR) to... more
False-negative severe acute respiratory syndrome coronavirus 2 test results can negatively impact the clinical and public health response to coronavirus disease 2019 (COVID-19). We used droplet digital polymerase chain reaction (ddPCR) to demonstrate that human DNA levels, a stable molecular marker of sampling quality, were significantly lower in samples from 40 confirmed or suspected COVID-19 cases that yielded negative diagnostic test results (ie, suspected false-negative test results) compared with a representative pool of 87 specimens submitted for COVID-19 testing. Our results support suboptimal biological sampling as a contributor to false-negative COVID-19 test results and underscore the importance of proper training and technique in the collection of nasopharyngeal specimens.