title: CCL5/RANTES gene deletion attenuates opioid-induced increases in glial CCL2/MCP-1 immunoreactivity and activation in HIV-1 Tat-exposed mice.
abstract: To assess the role of CC-chemokine ligand 5 (CCL5)/RANTES in opiate drug abuse and human immunodeficiency virus type 1 (HIV-1) comorbidity, the effects of systemic morphine and intrastriatal HIV-1 Tat on macrophage/microglial and astroglial activation were assessed in wild-type and CCL5 knockout mice. Mice were injected intrastriatally with vehicle or Tat and assessed after 7 days. Morphine was administered to some Tat-injected mice via time-release implant (5 mg/day, s.c. for 5 days) starting at 2 days post injection. Glial activation was significantly reduced in CCL5(-/-) compared to wild-type mice at 7 days following combined Tat and morphine exposure. Moreover, the percentage of 3-nitrotyrosine immunopositive macrophages/microglia was markedly reduced in CCL5(-/-) mice injected with Tat +/- morphine compared to wild-type counterparts, suggesting that CCL5 contributes to nitrosative stress in HIV-1 encephalitis. In CCL5(-/-) mice, the reductions in Tat +/- morphine-induced gliosis coincided with significant declines in the proportion of CCL2/MCP-1-immunoreactive astrocytes and macrophages/microglia compared to wild-type counterparts. In knockout mice, neither Tat alone nor in combination with morphine increased the proportion of CCL2-immunoreactive astrocytes above percentages seen in vehicle-injected controls. Macrophages/microglia differed showing modest, albeit significant, increases in the proportion of CCL2-positive cells with combined Tat and morphine exposure, suggesting that CCL5 preferentially affects CCL2 expression by astroglia. Thus, CCL5 mediates glial activation caused by Tat and morphine, thereby aggravating HIV-1 neuropathogenesis in opiate abusers and non-abusers. CCL5 is implicated as mediating the cytokine-driven amplification of CCL2 production by astrocytes and resultant macrophage/microglial recruitment and activation.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Richmond, VA 23298-0613, USA.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D018932:Chemokine CCL2 / Q000276:immunology* / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015897:Comorbidity; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D015658:HIV Infections / Q000276:immunology; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019966:Substance-Related Disorders / Q000276:immunology / Q000821:virology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000701:Analgesics, Opioid; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine