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
Kowatsch, Monika M
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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.
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