Development of HIV encephalitis in AIDS and TNF-α regulatory elements

Abstract

Tumor necrosis factor-α (TNF-α) appears to play an important role in HIV encephalitis (HIVE). TNF2, a polymorphism of TNF-α, associates with higher levels of TNF-α and severe manifestations of some infections. We studied 44 acquired immunodeficiency syndrome (AIDS) patients with autopsy-proven HIVE and/or HIV leukoencephalopathy (HIVLE) (HIVE/LE) and 30 AIDS patients without HIVE/LE. TNF2 did not associate with presence of HIVE/LE (p>0.5). Moreover, the TNF-α regulatory element TTATTTAT within the 3′-untranslated region was intact in HIVE/LE brains, and HLA-DR3 did not associate with HIVE/LE. Other host factors or, more likely, viral factors may be responsible for the development of HIVE/LE.

Introduction

Human immunodeficiency virus (HIV) encephalitis (HIVE) and HIV leukoencephalopathy (HIVLE) are the two main HIV specific brain lesions. They occur in 10–38% of acquired immunodeficiency syndrome (AIDS) brains at autopsy (Budka, 1991). Definite diagnosis of HIVE and/or HIVLE (HIVE/LE) is possible only by histopathological examination, because clinical symptoms of the HIV-1 cognitive/motor complex sometimes do not correlate with histopathology (Budka, 1991). Pathologically, HIVE is characterized by multiple disseminated foci composed of microglial cells, macrophages and multinucleated cells, whereas HIVLE features diffuse damage to the white matter including myelin loss with reactive astrogliosis, macrophages and multinucleated cells (Budka, 1991).

The damaging factor in HIVE/LE does not seem to be HIV itself, but cytokines mainly produced by monocytes/macrophages/microglial cells. In brain tissue, HIV appears to harbour and replicate in these cells, but not in astrocytes, oligodendrocytes, neurons, and endothelial cells (Nottet and Gendelman, 1995). The profile of cytokine production elicited by HIV seems to be a major cause of HIV specific neuropathology (Nottet and Gendelman, 1995). Tumor necrosis factor-α (TNF-α), a principal mediator of natural immunity mainly produced by mononuclear phagocytes, is likely to play an important role. TNF-α and TNF-α mRNA are elevated in brains with HIVE (Achim et al., 1993; Wesselingh et al., 1993). Moreover, TNF-α causes death of neurons and oligodendrocytes in vitro (Nottet and Gendelman, 1995).

The TNF-α gene lies in the MHC class III region (Wilson et al., 1995). TNF-α production is genetically regulated mainly by the promoter region and a TTATTTAT element within the 3′-untranslated region (3′-UTR) (Jongeneel, 1994). A single base polymorphism within the promoter region of TNF-α appears to correlate with TNF-α production: an allele with guanine at position -308 is referred to as TNF1, and with adenine at this position as TNF2; the latter is associated with higher TNF-α expression (Wilson et al., 1995). TNF2 is strongly linked to HLA-A1, B8, DR3 haplotypes in the European population (Wilson et al., 1995) which are known as markers for rapid progression of AIDS (Kaslow et al., 1990). An in vitro study showed that stimulated mononuclear cells with HLA-DR3 produce more TNF-α than those with other HLA types (Campbell and Milner, 1993; Wilson et al., 1995).

It has remained enigmatic why some AIDS patients develop HIV specific neuropathology and others do not. This study investigates TNF-α regulatory elements for their ability to influence the development of HIVE/LE.