To investigate neuropathological processes involved in HIV infection, a longitudinal analysis of central nervous system (CNS) changes was performed using the SIV-infected macaque model. Five animals were studied during the early phase and 13 during the asymptomatic and symptomatic phases. Histopathological analyses were performed on one cerebral fixed hemisphere whereas on the other frozen hemisphere in situ hybridisation, immunohistochemistry and RT-PCR were performed. Viral load was quantified by in situ hybridisation, CD4 and CD8 T cell infiltration by immunohistochemistry and mRNA cytokine expression (IL1beta, IL2, IL6, TNFalpha, IFNgamma and TGF-beta1) by semiquantitative RT-PCR. As reported for HIV-infected humans, the neuropathological analysis of SIV infected animals revealed four distinct lesion profiles: minimal changes, early encephalitis, leukoencephalopathy and encephalitis. No relationship was found between neuropathological findings, numbers of SIV replicating cells and T cell infiltration. CNS infection was found to be an early event characterised by glial activation, an increase in the level of IL1beta, TNFalpha and IL6 mRNA expression. During the asymptomatic and symptomatic phases, IL6 and IL1beta mRNAs increase coincided with gliosis and the development of myelin lesions. The absence of relationship between neuropathological findings and viral load suggests that cerebral lesions are caused by an indirect mechanism. Inflammatory cytokine pattern associated with severe lesions show the key role of glial activation in the SIV neuropathological process.