The role of arachidonic acid in the regulation of nitric oxide synthase isoforms by HIV gp120 protein in astroglial cells

• We studied the role of arachidonic acid (AA) in NOS regulation by gp120 protein.
• gp120 increases AA through cytosolic phospholipase A2 (cPLA2) activation.
• gp120 inhibits constitutive NOS and subsequent NO release through cPLA2-derived AA.
• Constitutive NOS inhibition by gp120 is critical for allowing NF-κB activation.
• An inhibitor of cPLA2 slashes iNOS and IL-1β transcription induced by gp120.

HIV-associated neurocognitive disorder (HAND) is a common cognitive impairment in AIDS that affects 15 to 50% of adults infected with human immunodeficiency virus (HIV). Excessive amounts of nitric oxide (NO), as produced by inducible NO synthase (iNOS) upon exposure of activated microglia and astrocytes to cytokines and/or viral proteins (e.g., HIV tat and gp120), are assumed to contribute to neuronal abnormalities in HAND. Evidence exists supporting the notion that iNOS induction takes place after an early decline in physiological NO levels (i.e., NO released by constitutive NOS). Here, we demonstrate that HIV-1 gp120 is able to inhibit neuronal NOS through a cytosolic phospholipase A2 (cPLA2)-dependent arachidonic acid (AA) production, this response being critical for allowing activation of the transcriptional factor NF-κB and subsequent iNOS and interleukin-1β transcription in astroglial cells. In this context, AA seems to act as an upstream proinflammatory effector. In view of the pathogenic role of cPLA2 in HAND, a deeper insight into the molecular and cellular mechanisms of its modulation may be helpful in finding new drugs to manage cognitive impairment in HIV-1 patients.

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