Abstract
BackgroundIntegrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection. During HIV infection, macrophages can extravasate from the blood to the brain, while producing chemotaxic proteins and cytokines, which have detrimental effects on central nervous system cells. The main goal of this study was to understand the effects of raltegravir (RAL) on human brain macrophage production of immune-mediators when infected with HIV, but did not compare with other antiretroviral agents.MethodsPro-inflammatory cytokines, IFN-γ, IL-10, IL-12-p70, IL-1, IL-8, TNF-α, and IL-6 were measured simultaneously in tissue culture supernatants from primary brain derived macrophages, microglia. We tested the effects of RAL on markers of astrocytosis and neurite integrity in primary human neuroglial cultures.ResultsRAL administered at 20 nM effectively suppressed HIV infection in microglia over 9 days. Only IL-8, IL-10, and TNF-α were above the detection limit in the majority of samples and RAL significantly suppressed the rate of cytokine production in HIV-infected microglia. During RAL-alone, the rate of IL-8 secretion was higher.ConclusionsRAL did not affect neurite area but inhibited astrocyte growth in the neuroglial cultures. Exploring the effects of RAL on pro-inflammatory molecule production in brain macrophages may contribute to designing ARV neuroprotective strategies in chronic HIV infection.
Highlights
Integrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection
We found that RAL administered at 20 nM was effective at suppressing HIV infection in microglia (Figure 1) for at least 9 d
IL-8, IL-10, and Tumor necrosis factor (TNF)-α were above the detection limit
Summary
Integrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection. During HIV infection, macrophages can extravasate from the blood to the brain, while producing chemotaxic proteins and cytokines, which have detrimental effects on central nervous system cells. Chronic human immunodeficiency virus (HIV) infection has detrimental effects on central nervous system (CNS) neuronal health. The principal targets of productive HIV infection in the brain are microglia and monocyte derived macrophages [1,2,3,4]. There are several prevailing hypotheses for the mechanisms of neural damage in HIV: direct neurotoxic effect from viral proteins and neural damage via intracellular signaling and secondary neural damage from cytokines and chemokines from infected microglia and brain macrophages [12]. Drugs used to treat HIV have variable neurotoxic effects, as examined by MAP2
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