An, Shu Fang; (1997) Detection of HIV-1 DNA in brains of asymptomatic HIV-positive individuals and the role of cytokines in the pathogenesis of early changes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

While the role of human immunodeficiency virus (HIV) in producing damage to the central nervous system (CNS) is undisputed, the pathogenesis of the disorders associated with the infection still remain unclear. Suggested pathogenetic mechanisms include direct action of HIV or viral protein (gp120) or an indirect one, via products secreted by HIV-1-infected macrophages/microglia or other glial cells, one of which is represented by cytokines. Regarding the time of the infection at which cytokines become detectable in the brain very little is known. The aim of this study was to ascertain whether 1) the presence of HIV-1 DNA and microglial hyperplasia in the brain during the pre-AIDS stages of the infection is accompanied by enhanced expression of MHC class II antigens and by presence of cytokines; 2) brain damage, including neuronal loss via apoptosis, seen in brains of AIDS patients, is present at the pre-AIDS stage. The methods applied to the study include morphology, immunohistochemistry for detection of p24, MHC class II and cytokines, PCR and in situ end labelling. HIV-1 DNA, but not HIV-1 p24 antigen, was detected in 17 of the 36 brains of HIV-1 positive pre-AIDS individuals. Levels of HIV-1 DNA in this group are lower than those found in AIDS group. Microgliosis and astrogliosis are present in the majority of pre-AIDS individuals. In addition, macrophages, but not MGC, are seen in some of these cases. Elevated expression of MHC class II, tumour necrosis factor (TNF)-α, interleukin (IL)-Iα, IL-4 and IL-6, and presence of apoptotic cells have been demonstrated in pre-AIDS cases. These data demonstrate that the state of immune activation described in AIDS is already present at the pre-AIDS stage, during which cytokines may trigger the cascade of events leading to brain damage; they suggest that therapeutic strategies in HIV-1 positive individuals might have to be applied before they enter the AIDS stage.

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