TY - JOUR
T1 - Central nervous system expression of HIV-1 gp120 activates the hypothalamic-pituitary-adrenal axis
T2 - Evidence for involvement of NMDA receptors and nitric oxide synthase
AU - Raber, Jacob
AU - Toggas, Stephanie M.
AU - Lee, Sherina
AU - Bloom, Floyd E.
AU - Epstein, Charles J.
AU - Mucke, Lennart
N1 - Funding Information:
This work was supported by NIH Grants MH47680 (L.M.), NS34602 (L.M.), and AG 08938 (C.J.E.) and by a grant from the Markey Charitable Trust to the UCSF Program in Biological Sciences.
PY - 1996/12/15
Y1 - 1996/12/15
N2 - 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.
AB - 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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U2 - 10.1006/viro.1996.0664
DO - 10.1006/viro.1996.0664
M3 - Article
C2 - 8955056
AN - SCOPUS:0030589548
SN - 0042-6822
VL - 226
SP - 362
EP - 373
JO - Virology
JF - Virology
IS - 2
ER -