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BACKGROUND: We recently showed that acquired immunodeficiency syndrome (AIDS) dementia is associated with activated infection of microglia, neurons, and astrocytes by HIV-1. However, it is doubtful whether infection per se is responsible for the dramatic symptoms associated with AIDS dementia. The purpose of this study was to determine the histologic distribution of messenger RNAs (mRNAs) of several cytokines that have been implicated in AIDS pathogenesis and to correlate this expression pattern with the in situ localization of polymerase chain reaction (PCR)-amplified HIV-1 nucleic acids in the central nervous system (CNS). MATERIALS AND METHODS: HIV-1 DNA was detected by PCR in situ hybridization. HIV-1 RNA and cytokine expression, including tumor necrosis factor alpha (TNF), inducible nitric oxide synthetase (iNOS), and macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta mRNA were detected by reverse transcriptase (RT) in situ PCR. RESULTS: Amplified viral DNA was detected in each of the seven HIV-1-positive cases and in none of the five negative controls. In people with AIDS dementia, many HIV-1 DNA-positive cells were detected in regions of the CNS that corresponded to clinical symptomatology. In AIDS patients with minimal CNS involvement, rare HIV-1-infected microglial cells were noted. Viral RNA was detected primarily in cases of AIDS dementia. TNF, iNOS, MIP-1 alpha and MIP-1 beta expression localized to tissues from AIDS dementia cases where HIV-1 infected cells were plentiful. Colocalization experiments showed that these cytokines were transcribed mostly by viral-negative cells. CONCLUSIONS: These results suggest that two key elements in AIDS dementia are massive productive viral infection, involving microglia, neurons, and astrocytes, and concomitant stimulation of cytokine transcription in the neighboring uninfected cells.