Date of Award

January 2015

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Subject Area(s)

Medicine, Neurosciences

Abstract

Central nervous system (CNS) inflammation is a mediator of brain injury in HIV

infection. We studied the natural course of CNS inflammation in the early phase of

infection by analyzing soluble (neopterin) and cellular (CD38 and HLA-DR) markers of inflammation in CSF and blood of antiretroviral-naïve subjects identified as having primary HIV infection (less than one year since HIV transmission). Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and activated CD4+ and CD8+ T-cells (co-expressing CD38 and HLA-DR) in blood and CSF.

Eighty-one subjects enrolled at an average of 100 days after HIV transmission and had one to 13 visits over an average of 321 days. Based on a mixed-effects model, the longitudinal trajectory of CSF neopterin was associated with its baseline concentration with a cutoff of 21 nmol/l. In subjects with baseline levels less than 21 nmol/l, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P < 0.001), whereas it decreased by 6.7% in subjects with baseline levels above 21 nmol/l (n = 11; P = 0.001). In a subset with available flow cytometry data, the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P < 0.001) and 0.73 (P = 0.02) per 10 weeks, respectively.

In summary, neopterin levels and percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1

infection, suggesting an accrual of intrathecal inflammation, a major contributor to

neuropathology in HIV infection.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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