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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    ABSTRACT: HIV-1 clades (subtypes) differentially contribute to the neuropathogenesis of HIV-associated dementia (HAD) in neuroAIDS. HIV-1 envelop protein, gp120, plays a major role in neuronal function. It is not well understood how these HIV-1 clades exert these neuropathogenic differences. The N-methyl-D: -aspartate (NMDA) receptor-reduced glutamine synthesis could lead to secretion of neurotoxins such as arachidonic acid (AA) which plays a significant role in the neuropathogenic mechanisms in neuroAIDS. We hypothesize that clade B and C gp120 proteins exert differential effects on human primary astrocytes by production of the neurotoxin arachidonic acid. Our results indicate that clade B gp120 significantly downregulated NMDA receptor gene and protein expression, and level of glutamine while increasing expression of prostaglandin E2 (PGE(2)) and thromboxane A2 receptor (TBXA(2) R) compared to HIV-1 clade C gp120 protein. Thus, our studies for the first time demonstrate that HIV-1 clade B-gp120 protein appears to induce higher levels of expression of the neuropathogenic molecule cyclooxygenase-2 (COX-2)-mediated arachidonic acid by-products, PGE(2), and TBXA(2) R compared to HIV-1 clade C gp120 protein. These studies suggest that HIV-1 clade B and C gp120 proteins may play a differential role in the neuropathogenesis of HAD in neuroAIDS.
    Full-text · Article · Jun 2011 · Journal of NeuroVirology
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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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    ABSTRACT: Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.
    Full-text · Article · Sep 2010 · Journal of Neuroimmune Pharmacology
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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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    ABSTRACT: Individuals suffering from human immunodeficiency virus type 1 (HIV-1) infection suffer from a wide range of neurological deficits. The most pronounced are the motor and cognitive deficits observed in many patients in the latter stages of HIV infection. Gross postmortem inspection shows cortical atrophy and widespread neuronal loss. One of the more debilitating of the HIV-related syndromes is AIDS-related dementia, or HAD. Complete understanding of HIV neurotoxicity has been elusive. Both direct and indirect toxic mechanisms have been implicated in the neurotoxicity of the HIV proteins, Tat and gp120. The glutamatergic system, nitric oxide, calcium, oxidative stress, apoptosis, and microglia have all been implicated in the pathogenesis of HIV-related neuronal degeneration. The aim of this review is to summarize the most recent work and provide an overview to the current theories of HIV-related neurotoxicity and potential avenues of therapeutic interventions to prevent the neuronal loss and motor/cognitive deficits previously described.
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