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Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. This review will first discuss the spectrum of potential interactions between HIV-1 and neural (neuronal and glial) cells, in the face of experimental data. Next, we will focus on the role of immune-derived cytokines and other soluble compounds which have been proposed to act as neurotoxic mediators and appear to play a role in the pathogenesis of AIDS-associated neurodegeneration.

Previous studies indicated that the Tat protein of HIV functions as a progression factor in Kaposi's sarcoma (KS), an angioproliferative disease common and aggressive in HIV-1-infected individuals (AIDS-KS). In particular, Tat that is released by infected cells stimulates the growth and invasion of spindle cells of endothelial origin derived from KS lesions (KS cells). Other work suggested that inflammatory cytokines may act as initiating factors in KS since they induce normal endothelial cells to acquire the same phenotype and functional features of KS cells, including the responsiveness to Tat. In this study, we show that among the inflammatory cytokines increased in AIDS-KS lesions, IFN-gamma alone is sufficient to induce endothelial cells to proliferate and to invade the extracellular matrix in response to Tat. This is because IFN-gamma up-regulates the expression and activity of the receptors for Tat identified as the integrins alpha5beta1 and alpha(v)beta3. These results suggest that, by triggering Tat effects, IFN-gamma plays a major role in AIDS-KS pathogenesis.

Kaposi's sarcoma (KS) is a proliferative disease of vascular origin particularly frequent in HIV-1-infected homosexual men (AIDS-KS) and characterized by proliferating spindle-shaped cells, angiogenesis, and inflammatory cell infiltration. Previous work has suggested that KS spindle cells are of endothelial cell origin and that chronic immune activation via the release of inflammatory cytokines may cooperate with basic fibroblast growth factor (bFGF) and the HIV-1 Tat protein in the induction and progression of AIDS-KS. Here we show that KS spindle cells have features of activated endothelial cells, and that conditioned media from activated T cells, rich in the same inflammatory cytokines increased in HIV-1-infected individuals, induce normal endothelial cells to acquire the phenotypic and functional features of KS cells. These include (a) acquisition of a similar pattern of cell surface antigen expression; (b) similar proliferative response to bFGF; (c) induction of the responsiveness to the mitogenic effect of extracellular HIV-1 Tat protein that is now able to promote the G1-S transition of endothelial cell cycle; and (d) induction in nude mice of vascular lesions closely resembling early KS as well as the lesions induced by inoculation of KS cells. These results suggest that chronic immune activation, via release of inflammatory cytokines, may play a role in the induction of KS.

Kaposi's sarcoma (KS) is the most frequent tumor of HIV-1-infected individuals (AIDS-KS). Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells of KS, and endothelial cells forming blood vessels. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is highly expressed by KS spindle cells in vivo and after injection in nude mice it induces vascular lesions closely resembling early KS in humans. Similar lesions are induced by inoculating nude mice with cultured spindle cells from AIDS-KS lesions (AIDS-KS cells) which produce and release bFGF. Here we show that phosphorothioate antisense (AS) oligonucleotides directed against bFGF mRNA (ASbFGF) inhibit both the growth of AIDS-KS cells derived from different patients and the angiogenic activity associated with these cells, including the induction of KS-like lesions in nude mice. These effects are due to the block of the production of bFGF which is required by AIDS-KS cells to enter the cell cycle and which, after release, mediates angiogenesis. The effects of ASbFGF are specific, dose dependent, achieved at low (0.1-1 microM), nontoxic, oligomer concentrations, and are reversed by the addition of bFGF to the cells, suggesting that ASbFGF oligomers are promising drug candidates for KS therapy.

Basic fibroblast growth factor (bFGF) and human immunodeficiency virus type 1 (HIV-1) Tat protein synergize in inducing angiogenic Kaposi's sarcoma-like lesions in mice. Synergy is due to Tat, which enhances endothelial cell growth and type-IV collagenase expression in response to bFGF mimicking extracellular matrix proteins. The bFGF, extracellular Tat and Tat receptors are present in HIV-1-associated KS, which may explain the higher frequency and aggressiveness of this form compared to classical Kaposi's sarcoma where only bFGF is present.