Helene Cote


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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2021)
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 - 2020)
Placental Mitochondrial Dysfunction in relation to preterm delivery in HIV pregnancy (2018)

Background: Preterm birth (PTB) (1 million deaths in 2015 [1]. In North America, PTB occurs in 6–10% of births. However, among pregnant women living with HIV, the rates are higher (18-29%). To date, there is no generally accepted mechanism underlying such increased rates. One possible explanation is reduced maternal progesterone production during pregnancy, which may be related to HIV infection and/or antiretroviral (ARV) treatment. Synthesis of progesterone (hormone central to pregnancy maintenance), is dependent on placental mitochondrial function. Given that many ARVs can affect mitochondrial (mt) function, I investigated the possible effects of ARV on placental mtDNA content and progesterone levels.Methods: 136 HIV+ and 60 HIV- pregnant women were enrolled in the Canadian prospective study, the Children and women: Antiretroviral and Markers of Aging (CARMA) cohort. Placenta and blood specimens, as well as clinical and sociodemographic data, were collected. Placental and plasma progesterone levels, as well as placenta mtDNA content, were measured using ELISA and qPCR respectively. We extended these investigations of ARV effects to in vitro models on two human placental cell lines, JEG-3 and BeWo.Results: Within this cohort, HIV-exposed uninfected (HEU) infants were born at an earlier gestational age (p=0.017), with a lower birth weight (p=0.011) compared to controls. PTB showed no association with HIV status, placenta mtDNA or progesterone levels. However, higher mtDNA was associated with preeclampsia (p
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Investigating Markers of Cellular Aging in Human Immunodeficiency Virus Infected and Uninfected Adults (2013)

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Measuring apparent oxidative damage to mitochondrial DNA to HIV antiretroviral therapy (2012)


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