Date of Award

January 2019

Document Type

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 (<12 months since 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<0.05). During follow up on ART, blood but not CSF T-cell activation declined with days on treatment (slope= -0.06, p=0.001). In conclusion, during untreated PHI, T-cell activation increases faster in CSF than blood, and CSF CD4+ T-cell activation but not monocyte activation correlates with CSF HIV RNA. Intrathecal T-cell activation does not decline during early follow up on ART. This study suggests a level of irreversibility to the neuroinflammation that develops in PHI, implicates CD4+ T cells as a likely source for trafficking HIV into the CNS, and highlights possible monocyte-T cell interactions that warrant further exploration.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 07/15/2021

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