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

Abstract

HIV-1 associated neurocognitive disorders (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 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 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.

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

“…They may be useful in the prevention and management of HAND especially in combating the metabolic effects of HIV and ART. 91 The increasing age of PLWH creates a higher risk of diabetes and heart disease which can compromise brain function. 38 Treatment of these co-morbid conditions can possibly increase BDNF levels and improve cognitive deficits.…”

Neuroendocrine Control of Macrophage Development and Function

“…In a murine model of traumatic brain injury, this drug inhibited microglia/macrophage activation and showed enhanced anti-inflammatory polarization ( 160 ). Interestingly, atorvastatin has been reported to downmodulate activation of a blood monocyte subset that seems to be involved in HIV-1-associated neurocognitive disorders ( 161 ). Since this compound can accumulate in the CNS, its effects on both recruited inflammatory monocytes and microglia have been a matter of clinical investigation ( , ID: NCT01600170).…”

Lower HDL-C levels are associated with higher expressions of CD16 on monocyte subsets in coronary atherosclerosis

“…Although CD14 was found to be positively correlated with HDL-C and negatively correlated with TC, there was no significant difference in CD14 expressions between the groups. As mentioned before, statins can affect CD14 expressions on monocytes [28,29], which may be the cause for the above results. However, the mechanism needs to be further explored.…”

“…Effects of statins on monocyte subsets vary from drugs. Simvastatin and atorvastatin can reduce CD14/CD16 expression on LPS-stimulated monocytes, causing reduced intermediate monocytes in vitro [28]. In addition, fluvastatin treatment in hypercholesterolemic patient leads to a decrease in CD14 expression, but an increase in more matured non-classical monocytes [29].…”