Statin modulation of monocyte phenotype and function: implications for HIV-1-associated neurocognitive disorders

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...

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Bibliographic Details
Published in:Journal of neurovirology 2016-10, Vol.22 (5), p.584-596
Main Authors: Yadav, Anjana, Betts, Michael R., Collman, Ronald G.
Format: Article
Language:English
Subjects:
AIDS Dementia Complex - genetics
AIDS Dementia Complex - immunology
AIDS Dementia Complex - pathology
Antigens, CD - genetics
Antigens, CD - immunology
Antigens, Differentiation, Myelomonocytic - genetics
Antigens, Differentiation, Myelomonocytic - immunology
Atorvastatin Calcium - pharmacology
Biomedical and Life Sciences
Biomedicine
Chemokine CCL2 - genetics
Chemokine CCL2 - immunology
Chemokine CCL2 - pharmacology
Chemokine CCL3 - genetics
Chemokine CCL3 - immunology
Chemotaxis
Gene Expression Regulation - drug effects
Gene Expression Regulation - immunology
GPI-Linked Proteins - genetics
GPI-Linked Proteins - immunology
Healthy Volunteers
Humans
Immunology
Infectious Diseases
Interleukin-8 - genetics
Interleukin-8 - immunology
Lentivirus
Lipopolysaccharide Receptors - genetics
Lipopolysaccharide Receptors - immunology
Lipopolysaccharides - antagonists & inhibitors
Lipopolysaccharides - pharmacology
Models, Biological
Monocytes - cytology
Monocytes - drug effects
Monocytes - immunology
Neurology
Neurosciences
Phenotype
Primary Cell Culture
Receptors, Cell Surface - genetics
Receptors, Cell Surface - immunology
Receptors, IgG - genetics
Receptors, IgG - immunology
Retroviridae
Signal Transduction
Simvastatin - pharmacology
Virology
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Description
Summary: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.
ISSN:1355-0284
1538-2443
DOI:10.1007/s13365-016-0433-8