Central Nervous System Expression of HIV-1 Gp120 Activates the Hypothalamic-Pituitary-Adrenal Axis: Evidence for Involvement of NMDA Receptors and Nitric Oxide Synthase

Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Virology (Impact Factor: 3.32). 01/1997; 226(2):362-73. DOI: 10.1006/viro.1996.0664
Source: PubMed


The impact of HIV-1 expression in the brain on the development of AIDS is unknown. In the present study, we examined the hypothalamic-pituitary-adrenal (HPA) axis in a transgenic model in which expression of the HIV-1 envelope glycoprotein gp120 induced central nervous system (CNS) damage similar to that seen in HIV-1-infected patients. Compared with nontransgenic littermates, gp120 transgenic mice showed significant increases in plasma corticosterone and adrenocorticotrophic hormone (ACTH) levels and pituitary ACTH content. To determine whether this activation of the HPA axis could be mediated by ACTH secretagogues, the effect of recombinant gp120 on the release of these factors from hypothalamic slices was investigated in vitro. Recombinant gp120 induced release of the ACTH secretagogue arginine vasopressin from nontransgenic hypothalamic slices in a calcium-dependent fashion. This effect was inhibited by antagonists of N-methyl-D-aspartate (NMDA) receptors or of nitric oxide synthase (NOS), suggesting a role for NMDA receptor stimulation and NOS activity. Further evidence for a role of free radicals was obtained from bigenic mice coexpressing gp120 and the free radical scavenger human copper/zinc superoxide dismutase which showed normal corticosterone levels. This might relate to superoxide dismutase-mediated scavenging of superoxides generated by NOS. These findings demonstrate that CNS expression of a viral envelope protein can activate the HPA axis and thereby alter peripheral levels of immunomodulatory hormones.

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Available from: Jacob Raber, Aug 06, 2014
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    • "The HIV-1 gp120 protein is required for viral entry into the host cells. It facilitates the viral replication and enhances neurotoxicity through inducible nitric oxide synthesis (Raber et al. 1996; Dawson et al. 1993), and causes cellular oxidative stress which progressively affects the central nervous system (CNS; Brenneman et al. 1994; Galicia et al. 2002). Gp120 binds to glutamate (Scorziello et al. 1998) and increases intracellular calcium levels (Dreyer et al. 1990), which eventually leads to lipid peroxidation (Corasaniti et al. 1998) causing " excitotoxic, " N-methyl-Daspartate (NMDA) receptor-mediated neuronal damage (Corasaniti et al. 1996; Lipton et al. 1991; Holden et al. 1999). "
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    • "Memantine is effective in gp120 transgenic mice and HIVE SCID mice. Furthermore, it appears to have some efficacy in clinical trials in patients with Alzheimer's Disease, another neurodegenerative disease associated with excitotoxicity (Raber et al. 1996; Anderson et al. 2004; Lipton and Chen 2003; Tariot et al. 2004), and is, in fact, currently FDA-approved for AD treatment. The neuroprotective potential for NMDAR antagonists such as memantine, in cases of HAND has recently been investigated in a therapeutic multicenter trial of Namenda (memantine ; Schifitto et al. 2007b). "
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    • "Activation and stimulation of the nitric oxide synthesis pathways has also been reported following exposure to gp120 [15]. Biomarkers of oxidative stress have consistently been detected in brain tissues and cerebrospinal fluid of patients with HIV-associated dementia [16]. "
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