Abstract
Neurocognitive impairments affect a substantial population of HIV-1 infected individuals despite the success of anti-retroviral therapy in controlling viral replication. Astrocytes are emerging as a crucial cell type that might be playing a very important role in the persistence of neuroinflammation seen in patients suffering from HIV-1 associated neurocognitive disorders. HIV-1 viral proteins including Vpr exert neurotoxicity through direct and indirect mechanisms. Induction of IL-8 in microglial cells has been shown as one of the indirect mechanism through which Vpr reduces neuronal survival. We show that HIV-1 Vpr induces IL-6 and IL-8 in astrocytes in a time-dependent manner. Additional experiments utilizing chemical inhibitors and siRNA revealed that HIV-1 Vpr activates transcription factors NF-κB, AP-1 and C/EBP-δ via upstream protein kinases PI3K/Akt, p38-MAPK and Jnk-MAPK leading to the induction of IL-6 and IL-8 in astrocytes. We demonstrate that one of the mechanism for neuroinflammation seen in HIV-1 infected individuals involves induction of IL-6 and IL-8 by Vpr in astrocytes. Understanding the molecular pathways involved in the HIV-1 neuroinflammation would be helpful in the design of adjunct therapy to ameliorate some of the symptoms associated with HIV-1 neuropathogenesis.
Highlights
HIV-1 associated neurocognitive disorders (HAND), which is attributed to the direct and indirect effects of HIV-1 penetration into the central nervous system (CNS) remains a major problem that adversely affects the quality of life in patients living with HIV-1 [1]
HIV-1 Vpr time-dependently induces the production of IL-6 and IL-8 in astrocytes
SVGA astrocytes were transfected with a plasmid encoding for HIV-1 Vpr, and the cells were harvested at 1, 3, 6, 12, 24, 48 and 72h post transfection to determine the mRNA expression levels of IL-6 and IL-8
Summary
HIV-1 associated neurocognitive disorders (HAND), which is attributed to the direct and indirect effects of HIV-1 penetration into the central nervous system (CNS) remains a major problem that adversely affects the quality of life in patients living with HIV-1 [1]. HIV-1 Vpr and IL-6/IL-8 Mechanism microglia and astrocytes, and subsequent release of neurotoxins is responsible for the neuronal damage and their demise [1,4] Neurotoxins such as viral proteins or pro-inflammatory cytokines have been shown in a variety of studies to have a profound effect on the viability of the neurons [5,6]. Apart from the entire virus, the associated viral proteins have been postulated to play a crucial role in formation of neuroinflammatory milieu in CNS [7]. These cytokines are secreted to combat the pathological insult, because of their ability to communicate and co-operate with other host and viral mediators, they can generate and intensify undesirable effects. Presence of cytokines such as IFN-γ helps the virus in productively infecting astrocytes that will otherwise show restricted infection [8]
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