Objective: In spite of effective antiretroviral therapy (ART), cognition is impaired in upwards of 35% of the HIV-infected population. We investigated a possible link between peripheral immune activation and brain metabolite concentrations.
Design and methods: Thirty-five HIV-seropositive (HIV+) and eight HIV-seronegative adults were recruited to this cross-sectional study. All HIV-positive patients were on ART or a treatment interruption. Participants were evaluated for monocyte gene expression, cognitive status, and brain metabolite concentrations using 4-Tesla short echo-time proton magnetic resonance spectroscopy. Absolute concentrations of brain metabolites in the frontal white matter (FWM), anterior cingulate cortex (ACC), and basal ganglia were derived and related to monocyte gene expression and global deficit scores.
Results: Analysis of monocyte gene arrays revealed an interferon (IFN)-α-induced activation phenotype. Fourteen genes having the greatest fold increase in response to HIV were IFN genes. Monocyte activation as measured by gene expression profiles strongly correlated with lower N-acetylaspartate (NAA) in FWM. The IFN response gene Interferon-gamma inducible protein-10 (IP-10) was activated in monocytes from HIV individuals and strongly correlated with plasma protein levels. Plasma IP-10 correlated significantly and inversely with ACC NAA, which was lower in HIV-positive patients with mild compared to no cognitive impairment.
Conclusion: Chronic peripheral immune activation driven by a type 1 IFN correlates with neuronal injury in FWM and ACC and cognitive dysfunction. Easily measured IFN-induced blood markers may be clinically significant in following early neural cell damage.
aDepartment of Laboratory Medicine, Veterans Affairs Medical Center
bDepartment of Laboratory Medicine and Medicine, University of California
cDepartment of Mental Health, Veterans Affairs Medical Center
dDepartment of Radiology and Biomedical Imaging, Center for Imaging of Neurodegenerative Diseases, Veterans Affairs Medical Center and University of California, San Francisco, California, USA.
Correspondence to Dr Lynn Pulliam, Veterans Affairs Medical Center, 4150 Clement St (113A), San Francisco, CA 94121, USA. Tel: +1 415 221 4810x6490; fax: +1 415 379 5647; e-mail: email@example.com
Received 11 March, 2011
Revised 4 June, 2011
Accepted 15 June, 2011