Enhanced expression of proinflammatory cytokines in the central nervous system is associated with neuroinvasion by simian immunodeficiency virus and the development of encephalitis

Abstract

Inflammatory cytokines are believed to play an important role in the pathogenesis of human immunodeficiency virus type 1-associated encephalitis. To examine this in the simian immunodeficiency virus (SIV)-infected macaque model of neuroAIDS, inflammatory cytokine gene expression was evaluated in the brains of macaques infected with pathogenic SIV(mac251) by reverse transcriptase PCR. Interleukin-1 beta was readily detected in the brains of all animals evaluated, regardless of infection status or duration of infection. Tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) transcripts were undetectable in the brains of uninfected control animals but were upregulated at 7 and 14 days postinoculation. At the terminal stage of infection, TNF-alpha and IFN-gamma transcripts were coexpressed in the brains of four of five animals with SIV encephalitis (SIVE). Within an encephalitic brain, TNF-alpha and IFN-gamma transcripts were detected in six of seven regions with histologic evidence of SIVE, suggesting a direct relationship between neuropathology and altered cytokine gene expression. With combined fluorescent in situ hybridization and immunofluorescence, TNF-alpha-expressing cells were frequently identified as CD68-positive macrophages within perivascular lesions. These observations provide evidence that cytokines produced by activated inflammatory macrophages are an important element in the pathogenesis of SIVE.

FIG. 1.

Demonstration of TNF-α transcripts in paraffin-embedded sections of brain from an SIV-infected macaque with SIVE. Many TNF-α⁺ cells are CD68⁺ macrophages (colocalized as yellow) located within a focus of inflammation. TNF-α transcripts are also evident within endothelial cells adjacent to the lesion and other cells within the neuropil. Bar = 10 μm.

FIG. 2.

Demonstration of IFN-γ transcripts by in situ hybridization on paraffin-embedded sections of brain from an SIV-infected macaque with SIVE. Isolated, intensely positive mononuclear cells, consistent with lymphocytes, are evident adjacent to small blood vessels (indicated by the letter V) (A) and within the subependyma (B).