title: Statin modulation of monocyte phenotype and function: implications for HIV-1-associated neurocognitive disorders.
abstract: HIV-1-associated neurocognitive disorder (HAND) remains a persistent problem despite antiretroviral therapy (ART), largely a result of continued inflammation in the periphery and the brain and neurotoxin release from activated myeloid cells in the CNS. CD14+CD16+ inflammatory monocytes, expanded in HIV infection, play a central role in the pathogenesis of HAND and have parallels with monocyte-dependent inflammatory mechanisms in atherosclerosis. Statins, through their HMG-CoA reductase inhibitor activity, have pleiotropic immunomodulatory properties that contribute to their benefit in atherosclerosis beyond lipid lowering. Here, we investigated whether statins would modulate the monocyte phenotype and function associated with HIV-1 neuropathogenesis. Treatment ex vivo with simvastatin and atorvastatin reduced the proportion of CD16+ monocytes in peripheral blood mononuclear cells, as well as in purified monocytes, especially CD14++CD16+ "intermediate" monocytes most closely associated with neurocognitive disease. Statin treatment also markedly reduced expression of CD163, which is also linked to HAND pathogenesis. Finally, simvastatin inhibited production of monocyte chemoattractant protein-1 (MCP-1) and other inflammatory cytokines following LPS stimulation and reduced monocyte chemotaxis in response to MCP-1, a major driver of myeloid cell accumulation in the CNS in HAND. Together, these findings suggest that statin drugs may be useful to prevent or reduce HAND in HIV-1-infected subjects on ART with persistent monocyte activation and inflammation.
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Department of Microbiology, University of Pennsylvania Perelman School of Medicine, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA. collmanr@mail.med.upenn.edu.|Department of Microbiology, University of Pennsylvania Perelman School of Medicine, 36th and Hamilton Walk, Philadelphia, PA, 19104, USA. collmanr@mail.med.upenn.edu.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D000069059:Atorvastatin / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology; D002633:Chemotaxis; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D064368:Healthy Volunteers; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D010641:Phenotype; D061251:Primary Cell Culture; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C111835:CCL2 protein, human; D000098902:CD163 Antigen; D018932:Chemokine CCL2; D054405:Chemokine CCL3; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D000069059:Atorvastatin; D019821:Simvastatin
keywords: HAND; Monocyte; NeuroAIDS; Statin