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

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dc.contributor.authorKowatsch, Monika M
dc.contributor.examiningcommitteeBall, Blake (Medical Microbiology and Infectious Diseases)en_US
dc.contributor.examiningcommitteeBay, Denice (Medical Microbiology and Infectious Diseases)en_US
dc.contributor.examiningcommitteeMignone, Javier (Community Health Sciences)en_US
dc.contributor.examiningcommitteeShoukry, Naglaa (University of Montreal)en_US
dc.contributor.supervisorFowke, Keith R
dc.date.accessioned2023-05-24T15:57:19Z
dc.date.available2023-05-24T15:57:19Z
dc.date.copyright2023-05-24
dc.date.issued2023-04-21
dc.date.submitted2023-05-19T16:10:30Zen_US
dc.date.submitted2023-05-24T15:27:55Zen_US
dc.degree.disciplineMedical Microbiology and Infectious Diseasesen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractIntroduction: 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.noteOctober 2023en_US
dc.description.sponsorshipGrand 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 studentshipen_US
dc.identifier.urihttp://hdl.handle.net/1993/37353
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectImmune responseen_US
dc.subjectSolvent useen_US
dc.subjectImmune quiescenceen_US
dc.subjectHIV preventionen_US
dc.subjectHIV risken_US
dc.subjectAcetylsalicylic aciden_US
dc.subjectHydroxychloroquineen_US
dc.subjectKnowledge Translationen_US
dc.titleThe effect of immune status on markers of HIV risk and prevention, immune quiescence, and immune activation: the teetertotter effect of the immune response and HIVen_US
dc.typedoctoral thesisen_US
local.subject.manitobayesen_US
oaire.awardNumberOCH # 126275en_US
oaire.awardTitleLimiting HIV target cells by inducing immune quiescence in the female genital tract; Operating Grant - PA: CHVI Vaccine Discovery and Social Researchen_US
oaire.awardURIhttps://cihrirsc.gc.ca/e/193.htmlen_US
project.funder.identifierhttps://doi.org/10.13039/501100000024en_US
project.funder.nameCanadian Institutes of Health Researchen_US
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