TMARC Pilot Studies - Completed

METH & Immune Senescence in Cerebrospinal Fluid (CSF) Cells in HIV Infection (Schrier)

Agency: TMARC
PI: Schrier, Rachel, Ph.D.

Abstract

Although up to 40% of HIV infected individuals have METH use histories, the effects on immune cells and trafficking have yet to be investigated. Study of T-cells from cerebrospinal fluid (CSF) of active METH users by flow cytometry indicates CD4 T-cells express higher levels of pro-inflammatory IFNg, and IL-2, compared to other peripheral blood CD4 cells, and to CSF lymphocytes from non METH users.  Also, METH alters lymphocyte distribution, increasing trafficking of activated (and HIV bearing?) T-cells into the CSF.  Although METH is known to activate monocytes in vitro, no studies have previously examined monocyte activation in CSF of METH users. Our hypothesis is that, in the HIV infected host with persistent activation of both monocytes and T-cells, chronic METH use increases and sustains activation and proliferation, independent of HIV RNA levels, contributing to immune exhaustion as defined by expression of CD57+28- and characterized by inflammatory cytokine (IFNg, IL-2, TNFa, IL-6) expression, but minimal protective functions (lysis and phagocytosis) by T-cells and monocytes, respectively. We hypothesize that the markers of immune senescence, cytokine expression, and HIV expression will be higher  in METH users compared to non METH users and higher in CSF, compared to PBMC because of METH accelerates trafficking of activated cells to CSF. In contrast, monocyte phagocytosis (of Ecoli) and T-cell lytic markers (CD107a) are predicted to be lower in chronic METH users. To test these hypotheses, CSF and PBMC from 20 TMARC participants with a history of at least 500 days of METH abuse during HIV infection (but not using within the last 6 months) and 20 HIV+ METH-controls, matched for CD4 and HIV RNA per the Behavioral Assessment and Medical (BAM) Core, will be evaluated for T-cell and monocyte surface and functional markers. Data gathered in this study of chronic METH use will be compared to that for acute METH use and serve as a basis for a larger study of the effects of METH on T-cell and monocyte inflammation, aging, and the HIV reservoir in the HIV infected host, using additional markers and including analysis of telomere length in specific lymphocyte subpopulations.

Sponsored by NIH/NIDA P50DA026306

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