The effect of immune status on markers of HIV risk and prevention, immune quiescence, and immune activation: the teetertotter effect of the immune response and HIV
dc.contributor.author | Kowatsch, Monika M | |
dc.contributor.examiningcommittee | Ball, Blake (Medical Microbiology and Infectious Diseases) | en_US |
dc.contributor.examiningcommittee | Bay, Denice (Medical Microbiology and Infectious Diseases) | en_US |
dc.contributor.examiningcommittee | Mignone, Javier (Community Health Sciences) | en_US |
dc.contributor.examiningcommittee | Shoukry, Naglaa (University of Montreal) | en_US |
dc.contributor.supervisor | Fowke, Keith R | |
dc.date.accessioned | 2023-05-24T15:57:19Z | |
dc.date.available | 2023-05-24T15:57:19Z | |
dc.date.copyright | 2023-05-24 | |
dc.date.issued | 2023-04-21 | |
dc.date.submitted | 2023-05-19T16:10:30Z | en_US |
dc.date.submitted | 2023-05-24T15:27:55Z | en_US |
dc.degree.discipline | Medical Microbiology and Infectious Diseases | en_US |
dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
dc.description.abstract | Introduction: In 2021, 1.5 million new Human Immunodeficiency Virus (HIV) infections occurred. Inflammation increases HIV risk; decreased inflammation is associated with protection in HIV-exposed seronegative (HESN) individuals who remain HIV seronegative despite repeated exposures. Understanding how behaviours/interventions alter inflammation is crucial and is the basis of this thesis. Aim 1: The Sniffing Around the Issue Study (SUS, 2015-2023) assessed the effect of solvent use on inflammation. Aim 2: The Inducing Immune Quiescence Study (IIQ, 2013-2022) assessed the ability of anti-inflammatory drugs, acetylsalicylic acid (ASA) and hydroxychloroquine (HCQ), to induce the HESN-like phenotype. Methods: Blood/plasma were collected in both aims. Aim 1: SUS enrolled 27 individuals – 14 solvent users and 13 community-matched controls. Immune cell phenotypes/functions, markers of microbial translocation, and cytokines/chemokines/hormones were measured. Aim 2: IIQ enrolled women (ASA:38, HCQ:39) with samples pre-/post-drug. Immune cell phenotypes/functions, antibody levels, oxylipin levels, and in vitro phosphorylation and cell migration were assessed. Both studies utilized integrated knowledge translation and community engagement which required pre-study/mid-study/post-study engagement. Results: Aim 1: Solvent users had increased natural killer (NK) cell activation, exhaustion, cytokine production, and degranulation with reduced KIR expression following stimulation. T cells exhibited altered cytokine response (increased on Th1 and Th1/Th17 and reduced on Th2 and CCR4+CCR6+ T cells) post stimulation. Solvent use reduced free thyroid hormone T3/T4 levels. For those in the IIQ study HCQ altered T cell trafficking, suppressed recall memory T cell responses, and decreased total IgG levels. ASA reduced T cell trafficking markers and total IgG levels. ASA enhanced recall memory T cell responses and NK activation without affecting NK function. ASA reduced levels of cyclooxygenase and the majority of lipoxygenase oxylipins and reduced mTOR/S6K phosphorylation which correlated with CCR5 expression. Conclusion: Solvent use decreased free thyroid hormone potentially explaining lethargy, increased NK cell inflammation and altered NK/T cell responsiveness to stimulation potentially increasing HIV risk. In the IIQ study, HCQ suppressed immune activation/memory T cell responses. ASA reduced immune cell activation without affecting memory T cell or NK cell responses potentially through altering oxylipins and mTOR phosphorylation supporting further investigation as a novel HIV prevention strategy. | en_US |
dc.description.note | October 2023 | en_US |
dc.description.sponsorship | Grand Challenges Canada (S5 386-01; https://www.grandchallenges.ca/) "Inducing immune quiescence"; project grant University Collaborative Research Program (UCRP #45581; https://doi.org/10.13039/100010318) “Sniffing around the issue: An investigation into the relationship between solvent use and HIV risk”; project grant Research Manitoba Graduate Fellowship (1928; www.researchmb.ca) "Determination if inducing immune quiescence through the use of antiinflammatory drugs modifies the immune response to recall antigens"; Masters Studentship Canadian Institutes of Health Research Doctoral Research Award - Priority Announcement: Research in First Nations, Métis and/or Inuit Health (201810DIA-417567-267854; https://doi.org/10.13039/501100000024) "Sniffing around the Issue: investigating the relationship between solvent use and HIV risk"; Doctoral studentship | en_US |
dc.identifier.uri | http://hdl.handle.net/1993/37353 | |
dc.language.iso | eng | en_US |
dc.rights | open access | en_US |
dc.subject | Immune response | en_US |
dc.subject | Solvent use | en_US |
dc.subject | Immune quiescence | en_US |
dc.subject | HIV prevention | en_US |
dc.subject | HIV risk | en_US |
dc.subject | Acetylsalicylic acid | en_US |
dc.subject | Hydroxychloroquine | en_US |
dc.subject | Knowledge Translation | en_US |
dc.title | The effect of immune status on markers of HIV risk and prevention, immune quiescence, and immune activation: the teetertotter effect of the immune response and HIV | en_US |
dc.type | doctoral thesis | en_US |
local.subject.manitoba | yes | en_US |
oaire.awardNumber | OCH # 126275 | en_US |
oaire.awardTitle | Limiting HIV target cells by inducing immune quiescence in the female genital tract; Operating Grant - PA: CHVI Vaccine Discovery and Social Research | en_US |
oaire.awardURI | https://cihrirsc.gc.ca/e/193.html | en_US |
project.funder.identifier | https://doi.org/10.13039/501100000024 | en_US |
project.funder.name | Canadian Institutes of Health Research | en_US |
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