SUBSTANCE P AND NEUROKININ-1 EXPRESSION IN THREE BRAIN REGIONS OF HIV-INFECTED INDIVIDUALS FROM THE NATIONAL NEUROAIDS TISSUE CONSORTIUM COHORT: Findings and Implications of Drug Use and Neuropathology In The Management Of NeuroAIDS

Abstract

INTRODUCTION: HIV- associated neurocognitive disorder (HAND) and pathology are common manifestations of HIV-infection, and often persist in spite of controlled peripheral viremia. Severity of HAND can range from loss of concentration and psychological changes to frank dementia. Inflammatory host-immune responses and chemotaxis of immune cells into the CNS are thought to be integral to development of NeuroAIDS and HAND. OBJECTIVES: This studies' primary aim was to determine if significant differences existed between Substance P and NK1R expression in brain tissue samples of HIV-infected individuals with neurocognitive disorder or pathology. The secondary aim was to determine whether expression of HIV viral entry receptors CCR5 and CXCR4 correlate with expression of Substance P or NK1R. The tertiary aim of this study was to determine if age at death, CNS penetration-effectiveness of antiretroviral therapy, diagnosis before HAART, average plasma CD4, or abnormal alcohol or drug use increased prevalence of neurocognitive disease. STUDY DESIGN: Cross-sectional study of HIV-infected individuals (n=60) from the larger National NeuroAIDS Tissue Consortium Cohort. Pre-death demographic data, neurocognitive assessment, alcohol and drug use, ART regimens, date of diagnosis and death, and plasma CD4 levels, as well as pathology findings at autopsy and brain tissue samples were provided by the NNTC; expression levels of Substance P, NK1R, CCR5, and CXCR4 from brain samples were provided by Dr. Steven Douglas of The Children's Hospital of Philadelphia. RESULTS: In this sample of HIV-infected individuals, Substance P expression was significantly less in the cingulate cortex of individuals with (p=0.003). Within-subject expression patterns of CCR5 and truncated-NK1R in the cingulate cortex and cerebellum were both significantly altered by neuropathology and cannabis use; CCR5 expression was also significantly affected by opiate use. CCR5 and CXCR4 expression correlated strongly with truncated-NK1R expression. No between-subject factors significantly altered prevalence of neurocognitive impairment in this HIV-infected population. CONCLUSIONS: The study found significant changes in Substance P, NK1R, and CCR5 expression associated with neuropathology. Furthermore, in heterogeneous populations, expression patterns may be more important than overall level of expression in identifying risk factors for NeuroAIDS and other chronic diseases.