Characterizing the effects of the kynurenine pathway on blood-brain barrier disruption and CD14+CD16+ monocyte function in people with HIV and comorbid depression

About This Grant

HIV is a major public health concern with 39.9 million people living with HIV as of 2023. Depression is the most common neuropsychiatric comorbidity seen in this population, affecting 30-50% of people with HIV (PWH), a prevalence almost two times greater than the general population. Depression in PWH is associated with increased morbidity and mortality. Thus, understanding the neurobiological mechanisms underlying depression in PWH is highly important. We propose that HIV-associated depression is mediated by activation of the kynurenine pathway (KP). Recent data from our group show that increased quinolinic acid (QUIN) and decreased kynurenic acid (KynA), both KP metabolites, are associated with depression and anhedonia severity in women with HIV, suggesting a role for the KP in depression pathogenesis in PWH. However, the mechanisms by which the KP drive depression pathogenesis are not characterized. We will examine mechanisms by which the KP contributes to depression in PWH. We hypothesize that the KP is mediating HIV-associated depression pathogenesis through its effects on the blood-brain barrier (BBB) and CD14+CD16+ monocyte function, which have both been implicated in depression and HIV neuropathogenesis. We will investigate this hypothesis with the following aims: Specific Aim 1: Assess the effect of KP metabolites on BBB permeability and function of CD14+CD16+ monocytes matured and infected with HIV in vitro. We will characterize mechanisms through which KP metabolites increase in vitro BBB permeability and transmigration and inflammatory function of CD14+CD16+ monocytes matured and infected with HIV in vitro. We will test effects of KYN, QUIN, and KynA on BBB permeability and TJP as a mechanism for BBB disruption. We will examine transmigration and inflammatory mediator production of KYN-treated in vitro matured and HIV-infected human CD14+CD16+ monocytes. Hypotheses: 1) QUIN, but not KynA, increases BBB permeability by altering BBB TJP; 2) KYN increases migration across the BBB and inflammatory mediators of CD14+CD16+ monocytes. Specific Aim 2. Examine the associations between peripheral KP activity, in vitro BBB permeability, CD14+CD16+ monocyte transmigration, and depressive symptom severity in PWH and PWoH. We will enroll 70 virally suppressed PWH and 70 PWoH and evaluate them for depression/anhedonia severity. Using plasma and PBMC from participants, we will assess peripheral KP activity, BBB permeability, and CD14+CD16+ monocyte transmigration. Multivariate analyses will determine associations of KP metabolites, BBB permeability, and PBMC transmigration with depression/ anhedonia severity in both groups. Hypothesis: Increased peripheral QUIN, decreased KynA, increased BBB permeability, and increased CD14+CD16+ monocyte transmigration will correlate with greater depression/ anhedonia severity in PWH. Impact: Understanding the effects of KP dysregulation on BBB integrity and monocyte function in the context of HIV and depression may identify targets to mitigate depression in PWH, enhancing quality of life and survival.