Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide

Abstract

The clinical manifestations of AIDS (acquired immune deficiency syndrome) often include neuropsychiatric and neurological deficits, including early memory loss and progressive dementia. HIV (human immunodeficiency virus), the aetiological agent of AIDS, is probably carried by infected macrophages in the central nervous system. The virus enters cells by binding its envelope glycoprotein gp120 to the CD4 antigen present on brain and immune cells. From the data reported in this paper, we now suggest that the neuronal deficits associated with HIV may not be entirely a result of infectivity, but that gp120 shed from HIV could directly produce the neuropathology as a result of its interference with endogenous neurotrophic substances. It is known that an analogue of a sequence contained in vasoactive intestinal peptide (VIP) occurs in all known sequenced gp120 isolates and that VIP is important for neuronal survival in cell culture. Here we show that purified gp120 from two diverse HIV isolates and a recombinant gp120 from a third isolate were all potent in specifically producing significant neuronal cell death in dissociated hippocampal cultures derived from fetal mice, and that this could be reduced by monoclonal antibodies against the murine CD4 antigen and completely antagonized by VIP.

HIV-1 gp120 receptor on CD4-negative brain cells activates a tyrosine kinase

“…Recent reports on the neurotoxicity of gp 120 in cell culture suggested that signal transduction through an unknown surface molecule may disturb cellular tunetians by raising intracellular Ca 2 + concentrations ( Brenneman et al, 1988;Dreyer et al, 1990;Kaiser et al, 1990;Pulliam et al, 1991 ). When we measured intracellular Ca 2 + concentrations in D-54 cells in response to 0.01 to 1 J.Lg/ml rgp120, no increase of Ca 2 + Ieveis could be detected (Fig.…”

“…ln AIDS patients, this mechanism has been suggested to be responsible forT helper cell depletion (Ameisen and Caprone, 1 991) and could also cause cellular dysfunction and atrophy as observed in the brain (Fauci, 1988). ln addition, the HIV envelope glycoprotein gp 120 has been shown to increase intracellular Ca 2 + concentrations tagether with NMDA receptor agonists and to injure rodent neurons in vitro (Brenneman et al, 1988;Dreyer et al, 1990;Lipton et al, 1991 ). These mechanisms and the observed tyrosine phosphorylation in response to rgp120 in glial cells could provide a combination of signals leading to astrocytosis, impairment of myelin, and neurodegeneration as found in brains of AIDS patients.…”

“…However, to mediate signals possibly leading to cellular dysfunction, entry of viruses into cells is not necessary, but rather the interaction of HIV-1 or gp 120 with cell surface receptors may be sufficient. lndeed, it was found that treatment of neuronal cultures of rodents with gp120 tagether with exitatory amino acids resulted in marked increases of intracellularcalcium and ultimately in neuronal cell death (Brenneman et al, 1988;Choi, 1988;Dreyer et al, 1990;Kaiser et al, 1990;Lipton et al, 1991 ). Theseobservations give certainly support to the hypothesis that soluble HIV-1 gp120 may interfere not only with neuronal, but also with glial cell functions and may be associated with the development of ADC.…”

“…Manifestations of ADC are progressive cognitive, motor, and behavioral dysfunctions that have been linked to the persistence of HIV-1 infections in the CNS and are mainly found in CD4-positive (CD4+) microglial cells and circulating macrophages (Budka, 1991;Fauci, 1988;Jordan et al, 1991;Ketzler et al, 1990;Liu et al, 1990;Maddon et al, 1986;McArthur, 1987;Merrill and Chen, 1991;Price et al, 1988). However, in the absence of CD4 molecules on the cell membrane of the majority of brain cells and in the light of the paucity of direct evidence for HIV infection of neurons and glial cells it has been suggested that the HIV-associated degenerative neurological abnormalities are the result of indirect mechanisms mediated by soluble factors of viral or cellular origin (Brenneman et a/., 1988;Dreyer et al, 1990;Giulian et al, 1990;Kaiser et al, 1990;Pulliam et al, 1991;Wahl et al, 1991 ). These factors could be cytotoxic to Subpopulations of brain cells or interfere with neuronal and glial cell functions leading to neurodegeneration.…”

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

“…7,26 These effects can be modeled in mixed neuronal/glial cerebrocortical cultures from rodents or humans in which purified or recombinant gp120 initiates neuronal injury and apoptosis. 3,7,11,17,18,27,28 In order to further dissect the role of chemokine receptors in HIV/gp120-induced neurotoxicity, we used mixed neuronal/ glial cerebrocortical cultures prepared from wild-type (WT) mice or rats, and mutant mice deficient in CXCR4, 29 CCR5 30 or both chemokine receptors. Our findings suggest that, depending on the viral strain, HIV/gp120 can utilize CCR5 or CXCR4 or both receptors for induction of neurotoxicity.…”