title: Does drug abuse alter microglial phenotype and cell turnover in the context of advancing HIV infection?
abstract: The aim of this study was to test the effects of drug abuse, in particular opiate abuse, on the phenotype and turnover of microglial cells within the brain in the context of advancing HIV infection. Basal ganglia and hippocampus sections were studied in 51 cases divided into six groups: HIV-negative normal controls, HIV-negative drug abusers, AIDS nondrug abusers, AIDS drug abusers, HIV encephalitis (HIVE) nondrug abusers and HIVE drug abusers. None of the cases studied had received highly active anti-retroviral therapy (HAART). Microglial phenotypes were defined using CD14, CD16, CD68 and major histocompatibility class II (MHC II). Microglial turnover was assessed using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) (DNA damage), BAX (proapoptotic marker), Fas (CD95) (proapoptotic), proliferating cell nuclear antigen (PCNA) (proliferation and DNA repair), Ki-67 (cell proliferation) and BCL-2 (antiapoptosis). We find increased expression of MHC II and CD16 in response to drug abuse. We also noted increased levels of TUNEL positivity in drug abusers compared to nondrug abusers, although conversely we found lower levels of BAX in those who had abused drugs. We find no evidence of microglial proliferation in any of our study groups, including HIVE, although HIV infection leads to increased expression of CD16, CD68 and MHC II. CD14 expression was restricted to perivascular microglia in all groups (including normal controls) apart from the two HIVE groups where some but not all cases also showed parenchymal expression of CD14. In contrast, CD16 was found in parenchymal microglia in all groups. Using high-pressure antigen retrieval and tyramide signal amplification, we find moderately high levels of CD16 expression in the parenchyma of normal brains which is not normally observed using standard avidin/biotin complex (ABC) techniques. This suggests that a low basal expression of CD16 occurs in many resident microglial cells which may potentially be upregulated in HIV-infected individuals. From these data, we suggest that not all the CD16+ parenchymal cells detected in AIDS brains (using ABC) represent influx of monocyte lineage cells from the blood. Finally the increased expression of MHC II and CD68 detected in drug abusers with HIVE compared to nondrug abusers with HIVE suggests that the combination of drug abuse and HIV infection has a greater deleterious effect on the brain than either individual insult on its own.
authors.affiliation: Neuropathology Unit, University of Edinburgh, Alexander Donald Building, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: I C
authors.initials: IC
authors.lastname: Anthony
authors.forename: S N
authors.initials: SN
authors.lastname: Ramage
authors.forename: F W
authors.initials: FW
authors.lastname: Carnie
authors.forename: P
authors.initials: P
authors.lastname: Simmonds
authors.forename: J E
authors.initials: JE
authors.lastname: Bell
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018792:Encephalitis, Viral / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology; D006681:HLA-D Antigens / Q000096:biosynthesis; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008297:Male; D017628:Microglia / Q000378:metabolism* / Q000821:virology; D008875:Middle Aged; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017452:Receptors, IgG / Q000096:biosynthesis; D019966:Substance-Related Disorders / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000096:biosynthesis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D006681:HLA-D Antigens; D019394:Ki-67 Antigen; D018950:Lipopolysaccharide Receptors; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D017452:Receptors, IgG; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C494826:BAX protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule