Date of Award

1-1-2019

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Abstract

Trafficking of immune cells to the central nervous system (CNS) is hypothesized to facilitate HIV entry and immune-induced neuronal injury, and is mediated by cell surface proteins such as chemokine receptors and integrins. We longitudinally assessed immune cell activation and surface marker expression in cerebrospinal fluid (CSF) and blood and their relationship with CSF HIV RNA during primary HIV infection (PHI) before and after combination antiretroviral therapy (ART). Longitudinal paired blood and CSF were obtained in initially ART-naïve PHI (infection) participants; some subjects independently initiated ART during follow up. Multiparameter flow cytometry was used to determine activation (% CD38+HLADR+) and chemokine receptor expression (% CCR5+ and CXCR3+) on CD4+ and CD8+ T cells, and subtype and α4 integrin expression (% and mean fluorescence intensity (MFI) of CD49d+) on monocytes. Analyses employed Spearman correlation and linear mixed models. A total of 51 participants enrolled at a median of 3.3 months post-infection, with 168 total visits (113 untreated, 55 on ART) during a median of 6.5 months follow up (range 0-40). Pre-ART, the rate of increase in T-cell activation was 3 times higher in CSF than blood. In univariate longitudinal analysis, both CSF CD4+ and CD8+ T-cell activation correlated with CSF HIV RNA (all p0.01); in multivariate analysis CSF CD4+ but not CD8+ T-cell activation¬ was an independent predictor of CSF HIV RNA. CSF monocyte subtypes and α4 expression did not correlate with CSF HIV RNA. Monocyte α4 MFI correlated with CD4+ and CD8+ T-cell activation in blood pre-ART, and in both CSF and blood while on treatment (all p

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