Helene Cote


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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2020)
HIV infection in the post-combination antiretroviral therapy era: a human model of immune aging (2020)

The deterioration of the immune system is a fundamental characteristic of aging and is accompanied by alterations in immune aging markers including shorter telomere length (TL), decreased mitochondrial DNA (mtDNA) content, and larger differentiated T cell populations. These same markers characterize an accelerated immune aging phenotype in people living with HIV (PLWH). Although HIV is successfully treated with combination antiretroviral therapy (cART), treatment is lifelong and does not fully eliminate the accelerated aging phenotype. Therefore, cART-controlled HIV infection can represent a human model of immune aging compared to the general population. The extent to which longitudinal changes in leukocyte TL (LTL) and blood mtDNA content inter-relate and are together influenced by HIV is unknown. Also unknown is whether slow progressors, a rare population who naturally control HIV without cART, are protected against HIV-mediated accelerated immune aging.The goal of my research was to investigate aging markers in PLWH, considering HIV infection as a human model of immune aging.First, I developed a monochrome multiplex quantitative PCR assay to measure mtDNA content quickly and accurately with low starting material. I measured blood mtDNA content, LTL, and their rates of change among 312 PLWH and 300 HIV-negative controls. I showed that faster rates of LTL attrition and blood mtDNA decline were associated with loss of HIV viral control. Faster LTL attrition was also associated with slower blood mtDNA content decline, regardless of HIV status. I then measured more granular markers of immune aging including lymphocyte subset TL and T cell differentiation in 57 slow progressors with sex- and age-matched cART-controlled PLWH and HIV-negative controls. My analyses revealed that slow progressors had shorter immune subset TL and more differentiated CD8 T cells compared to both cART-controlled PLWH and HIV-negative controls, indicating that they experience even faster immune aging despite naturally controlling the disease.My research confirms that uncontrolled chronic/latent viral infections such as HIV accelerate immune aging but demonstrates that naturally controlling HIV may also age immune cells. This suggests that preventing and controlling chronic/latent viral infections with therapy could extend lifespan and may represent an evolution to the paradigm of aging research.

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Dynamics of telomere length and mitochondrial health in relation to combination antiretroviral therapy (cART) exposure: a cohort study of HIV/cART-exposed uninfected children and cell culture investigations (2019)

Combination antiretroviral therapy (cART) during pregnancy has considerably reduced the risk of mother-to-child HIV transmission and the number of cART-exposed HIV-exposed uninfected (HEU) children is increasing. With current treatment guidelines recommending the initiation of immediate, lifelong cART at HIV diagnosis, women conceive on therapy and HEU in utero cART exposure spans the entire gestation period. Many antiretrovirals (ARV) cross the placenta and could exert long-term effects on HEUs. Some ARVs inhibit human telomerase reverse transcriptase (hTERT). As hTERT elongates telomeres and protects mitochondrial DNA (mtDNA) from oxidative damage, its inhibition could lead to shorter telomeres and/or increased mitochondrial dysfunction. Leukocyte telomere length (LTL) and mtDNA alterations are biomarkers of cellular aging, and have been implicated in aging and age-related diseases. The objective of my research was to compare HEU and HIV-unexposed uninfected (HUU) children at birth and in early life, with respect to their LTL and blood mtDNA content, and investigate relationships with in utero cART exposure. I measured LTL and blood mtDNA content in 324 HEU and 306 HUU children between 0-3y of age. I found that exposure to maternal cART did not affect LTL at birth, as it was similar in both groups. However, mtDNA content was higher among HEU children, particularly those exposed to boosted-protease inhibitor (PI/r) cART. This increase in mtDNA persisted at least up to age three. Additionally, maternal smoking during pregnancy affected both LTL and mtDNA content at birth. Given these effects of cART on children’s mtDNA, I aimed to further characterize how various cART regimens affect mitochondrial health using an in vitro human cell culture model. I also investigated the potential mitochondrial protection conferred by hTERT. I found that dolutegravir (DTG)-containing regimens negatively affected mitochondria, decreased cell proliferation and increased apoptosis. PI/r-containing regimens also affected certain mitochondrial parameters, but this effect was mitigated by mitochondrial hTERT while that of DTG was not. DTG is increasingly used worldwide, including in pregnancy. These novel findings merit further investigations to evaluate the long-term safety of newer ARV exposure, and the predictive value of these biomarkers on HEU health outcomes. Together, this knowledge could inform treatment guidelines.

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Master's Student Supervision (2010 - 2018)
Exploring mitochondrial DNA abnormalities in HIV-exposed uninfected children diagnosed with autism spectrum disorder: a case control study (2016)

Background: Antiretroviral therapy has reduced mother-to-child HIV transmission from 25-40% to less than 2%. Thus, increasing numbers of HIV-exposed uninfected (HEU) children are being born with perinatal exposure to antiretrovirals. Recently, a Canadian HIV clinic noticed a high prevalence of autism spectrum disorder (ASD) in HEU children. This prompted our analysis of HEU children enrolled in the pan-Canadian Children & Women AntiRetrovirals & Markers of Aging (CARMA) cohort study. Significant differences in mitochondrial DNA to nuclear DNA ratio (mtDNA content) have been observed in ASD children and HEUs as a potential marker for mitochondrial dysfunction, which has been theorized as a possible mechanism underlying abnormal neurodevelopment. We hypothesized that HEU children with ASD would have significantly different leukocyte mtDNA content than HEU children without ASD and/or HUU children with and without ASD.Methods: CARMA HEU children with ASD (n=14) were matched 1:3 on age, sex, and ethnicity to HEU children without ASD (n=42), HUU anonymous controls (n=42), and HUU children with ASD in the BC Autism Spectrum Interdisciplinary Research (ASPIRE) program (n=42). Non-ASD HUU siblings of ASD children (n=9) were also studied and grouped with the HUU controls for the purposes of analyses (n=51 total). MtDNA content was assessed using qPCR.Results: Among 299 HEU children in CARMA, 14 (4.7%) were diagnosed with ASD, substantially (>3-fold) above North American prevalence estimates (1.5%).HEU children with ASD had higher mtDNA content (median[interquartile range]: 163[150–179]) than non-ASD HEUs (115[91–153], p=0.02), HUUs with ASD (110[99–132], p=0.0001), and HUU controls (100[73–121], p
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Investigating Markers of Cellular Aging in Human Immunodeficiency Virus Infected and Uninfected Adults (2013)

Background: Despite successful combination antiretroviral therapy (cART), people living with HIV have shorter lifespans than the general population. Leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) oxidative damage are two frequently studied markers of aging that have recently been linked. Telomerase extends telomeres in highly proliferative tissues and is believed to play a protective role against oxidative stress in mitochondria. Given that both HIV and cART have the potential to accelerate cellular aging processes, we sought to measure LTL and mtDNA apparent oxidative damage (AOD) in the context of HIV infection and treatment.Methods: Demographic and clinical data and whole blood were collected from adults aged 19-75 enrolled in a prospective cohort on HIV therapy and aging (CARMA). LTL were measured by qPCR. Variables statistically correlated with LTL on univariate analysis (p
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Measuring apparent oxidative damage to mitochondrial DNA to HIV antiretroviral therapy (2012)

Background/objectives: HIV antiretroviral therapy, specifically nucleoside reverse transcriptase inhibitors (NRTIs) have been associated with mitochondrial DNA (mtDNA) alterations, possibly through mtDNA oxidative damage leading to mitochondrial dysfunction, which is associated with degenerative diseases and aging. A published assay exploits that oxidative damage can slow down/inhibit DNA polymerase progression, such that the PCR amplification of damaged mtDNA template yields less product compared to undamaged mtDNA. I sought to optimize this assay using in-house tools and to quantify apparent mtDNA oxidative damage in cultured cells exposed to NRTIs.Methods: Three DNA quantification methods were compared: PicoGreen fluorescence quantification, UV spectrophotometry, and qPCR mtDNA copy number. Human hepatocellular carcinoma cells (HepG2) were exposed to hydrogen peroxide (H₂O₂) followed by recovery time to allow mtDNA repair. To determine whether NRTI exposure induces mtDNA damage, human coronary artery endothelial cells (hCAE) cells and human colorectal adenocarcinoma cells (HT29) cells that had been exposed to various NRTIs were subjected to the assay. To assess the assay’s future applicability to clinical samples, human skeletal muscle DNA samples were also assayed.Results: Quantification of long PCR mtDNA product by UV (CV=6.5%) and qPCR (CV=7.0%) showed lowest variability while PicoGreen quantification was noticeably higher (CV=21%). DNA from H₂O₂-exposed cells showed decreased amplification of long PCR product that increased with repair time. MtDNA depletion occurred in both cultures treated with stavudine. While there was no apparent mtDNA oxidative damage in HT29 cells with any NRTI, both tenofovir and stavudine yielded increased mtDNA oxidative damage in hCAE cells. A wide degree of apparent mtDNA oxidative damage was observed in clinical samples.Conclusions: The preferred method for DNA quantification is qPCR mtDNA copy number. The observed mtDNA depletion indicated that NRTIs were active in both cell lines. The primary hCAE cells incurred greater mtDNA oxidative damage than cancer-derived HT29 cells. Cancer cells may have enhanced anti-oxidant mechanisms, suggesting that primary cells may be better model for studying mtDNA damage. The broad range of mtDNA damage detected in clinical samples bodes well for the assay’s use with diverse samples.

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Blood telomere length in infants and their HIV-infected mothers exposed to antiretroviral therapy during pregnancy (2011)

Background/Objectives:Nucleoside reverse transcriptase inhibitors (NRTIs) are part of the antiretroviral therapy (ART) given to HIV-infected pregnant women to prevent vertical HIV transmission. The NRTI zidovudine (AZT) is a known inhibitor of human telomerase, the enzyme responsible for telomere elongation. We hypothesized that average telomere length (ATL) may be shorter in infants born to HIV-infected mothers and exposed to ART in utero, compared to ART-unexposed infants.Methods:Two independent cohorts of pregnant women and their infants were studied, spanning 1990-2000 (SJ) and 2005-2009 (Pregnancy). SJ included 120 HIV⁺ exposed and unexposed pregnancies while Pregnancy included 99 HIV⁺ highly active antiretroviral therapy (HAART)-exposed and HIV⁻ pregnancies. Dried blood spots (SJ) or whole blood (Pregnancy) were collected from the pregnant women and their infants. Relative ATL (rATL) was measured by quantitative PCR. The differences in rATL between HAART/ART-exposed and unexposed maternal, infant and cord blood (CB) were investigated using ANCOVA, adjusting for maternal age, gestational age, smoking (cigarette/marijuana) and illicit drug/methadone use ever in pregnancy. For the HIV/HAART group, additional parameters included CD4+ count, HIV plasma viral load near delivery, length of HAART exposure, HCV infection and ethnicity. Relationships between maternal and infant rATL were also investigated.Results:Infant rATL were significantly longer than maternal rATL for both cohorts (p
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Blood mitochondrial DNA mutations in HIV-infected women and their infants exposed to HAART during pregnancy (2010)

Background/Objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) as part of highly active antiretroviral therapy (HAART) are given to human immunodeficiency virus (HIV)-infected pregnant women to prevent HIV vertical transmission. NRTIs can adversely affect mitochondrial DNA (mtDNA) and may induce mtDNA point mutations. We hypothesised that HAART-exposed/HIV-uninfected infants may show higher blood mtDNA mutation burden than controls born to HIV-uninfected mothers.Methods: Blood was collected from infants exposed in utero to HIV/HAART and controls (0-6d), as well as from a subset of their mothers (last visit before delivery). MtDNA mutation burden was measured by an assay involving cloning and sequencing mtDNA D-loop PCR amplicons. The presence of transversion mutations A → C/T → G (AC/TG) was analysed by Chi-squared and Wilcoxon signed-rank tests. Relationships with amount of DNA assayed, maternal age, smoking (marijuana/cigarettes) and illicit drug/methadone use in pregnancy were examined. For the HIV/HAART group, relationships with CD4+ count and HIV plasma viral load (pVL) near delivery, as well as length of HAART exposure were also examined.Results: The Taq error rate from PCR caused a low signal (mutation) to noise (background) ratio. Therefore, only AC/TG mutations, not induced under our assay conditions, were analysed. No significant difference was found between the percentage of HIV/HAART-exposed infants with AC/TG mutations (N=15/57, 26.3%) and controls (N=10/70, 14.3%) before (p=0.090) or after (p=0.058) controlling for covariates, although a trend was observed. Furthermore, significantly more HIV/HAART-exposed mothers (N=18/42, 42.9%) harboured AC/TG mutations compared to controls (N=7/39, 17.9%) both before (p=0.015) and after (p=0.012) controlling for covariates. AC/TG mutations were more prevalent in HIV/HAART-exposed mothers than in their infants (N=42, 42.9% vs. 23.8% p=0.033), however, this difference disappeared after controlling for covariates (p=0.777). No difference was observed between control mothers and their infants (N=39, both 17.9%). In HIV/HAART-exposed group mothers, only a detectable HIV pVL near delivery predicted AC/TG mutations.Conclusion:A subset of mtDNA mutations can be quantified with the developed assay. HIV/HAART exposure in pregnancy may be associated with increased prevalence of maternal mtDNA mutations. Since mtDNA mutations have been linked with aging and age-associated diseases, this raises concerns about the long-term impact of HAART.

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