HIV-gp120 affects the functional activity of oligodendrocytes and their susceptibility to complement

Abstract

The aim of this study was to assess whether the HIV protein gp120 can induce direct or/and indirect damage to oligodendrocytes (OL). Using highly purified cultures of rat OL, we report that gp120 binds to OL and induces functional alterations in these cells. Indeed, the percentage of cells expressing myelin basic protein (MBP) and the levels of all four MBP isoforms were substantially reduced after a 3-day treatment with 10 nM gp120. As gp120 depressed the ability of OL to reduce the tetrazolium salt MTT (a sign of mitochondrial impairment), the alteration of MBP production may be a consequence of decreased metabolic activity. The above effects were accompanied by a small increase in the number of apoptotic nuclei (from 4.3% in controls to 17.6% in cells treated for 3 days with gp120). As complement can lyse OL and gp120 is known to activate complement, we also studied the interaction between these two factors using OL cultures. The viral protein potentiated (by about 25%) the lytic effect of complement, when administered to the cultures 5 hr after complement, and depressed it (by about 30-40%), when added 5 hr before complement. Heat denaturation and anti-gp120 antibodies prevented the direct effect of gp120 on OL, but did not influence the interactions between gp120 and complement. Some gp120 non glycosylated peptides (V3 loop, 254-274 and 415-435 peptides) mimicked the ability of gp120 to antagonize the lytic effect of complement, but not that of potentiating complement lytic activity. In conclusion, our study indicates that gp120 can alter OL functional activity directly and can interfere with OL susceptibility to complement mediated lysis.

Human Immunodeficiency Virus Infection of the Brain: Pitfalls in Evaluating Infected/Affected Cell Populations

“…In one report brain tissue from AIDS patients showed structures that were ultrastructurally similar to retrovirus budding from a possible oligodendrocyte (58). Virions have also been detected in extracellular spaces surrounded by myelin sheath (66) consistent with HIVgp120 envelope protein binding to oligodendrocytes (16). Without optimal morphological preservation or immunolabeling with cell specific markers, it is difficult to use electron microscopy and resolve the lineage of cells containing budding virus.…”

Mechanisms of damage to myelin and oligodendrocytes and their relevance to disease

“…Spinal fluid levels of nitric oxide metabolites are increased in multiple sclerosis as well as in other inflammatory neurological diseases [ 68]. In multiple sclerosis lesions, abundant cNOS and iNOS expression in macrophages and perivascular microglia [ 7, 46] and in astrocytes [ 13] has been described.…”

Pathobiology of CNS Human Immunodeficiency Virus Infection

“…41 Myelin damage appears to be due to both primary viral proteinmediated damage and the effects of virally induced innate immune dysregulation. 43 The most common HIV-associated pathology in the spinal cord is a vacuolar myelopathy, which is characterized histopathologically by vacuolation of the lateral corticospinal tracts and dorsal columns with a heavy burden of lipid-laden macrophages but no axonal loss. In CNS HIV infection, increases in free radical nitric oxide (⋅NO) metabolites have also been demonstrated, 42 which in demyelinating disease have been implicated in oligodendrocyte damage and death.…”