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The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the alpha5beta1 and alphavbeta3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.

Kaposi's sarcoma (KS) is an angioproliferative disease associated with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and cyclin D, which can potentially transform the host cell. However, the expression of these genes in KS tissues is very low or undetectable and HHV-8 does not seem to transform human cells in vitro. In addition, KS may not be a true cancer at least in the early stage. This indicated that besides its transforming potential, HHV-8 may act in KS pathogenesis also through indirect mechanisms. Evidence suggests that KS may start as an inflammatory-angiogenic lesion mediated by cytokines. However, little is known on the nature of the inflammatory cell infiltration present in KS, on the type of cytokines produced and on their role in KS, and whether this correlates with the presence of HHV-8. Here we show that both acquired immunodeficiency syndrome (AIDS)-KS and classical KS (C-KS) lesions are infiltrated by CD8+ T cells and CD14+/CD68+ monocytes-macrophages producing high levels of gamma-interferon (gamma IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. gamma IFN, in fact, induces endothelial cells to acquire the same features of KS cells, including the spindle morphology and the pattern of cell marker expression. In addition, endothelial cells activated by gamma IFN induce angiogenic lesions in nude mice closely resembling early KS. These KS-like lesions are accompanied by production of basic fibroblast growth factor, an angiogenic factor highly expressed in primary lesions that mediates angiogenesis and spindle cell growth. The formation of KS-like lesions is upregulated by the human immunodeficiency virus Tat protein demonstrating its role as a progression factor in AIDS-KS. Finally, gamma IFN and HLA-DR expression correlate with the presence of HHV-8 in lesional and uninvolved tissues from the same patients. As HHV-8 infects both mononuclear cells infiltrating KS lesions and KS spindle cells, these results suggest that HHV-8 may elicit or participate in a local immune response characterized by infiltration of CD8+ T cells and intense production of gamma IFN which, in turn, plays a key role in KS development.

Evidence indicates that, at least in the early stage, Kaposi's sarcoma (KS) is a cytokine-mediated disease and that it is consistently associated with a novel herpesvirus termed human herpesvirus-8 (HHV-8). To gain insights into the mechanisms by which cytokines and HHV-8 may cooperate in disease pathogenesis, we examined the phenotype, the Th1 (gamma-interferon [gamma IFN]) and Th2 (interleukin-4 [IL-4] cytokine profile and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC), tumor-infiltrating lymphocytes (TIL), and spindle cell cultures derived from skin lesions of patients affected by classical KS (C-KS) and acquired immunodeficiency syndrome (AIDS)-associated KS (AIDS-KS). TIL and spindle cell cultures were examined at day 0 or after culture in conditioned media from activated T cells (TCM) that contain the same cytokines increased in KS tissues. No differences were found in the immunophenotype of PBMC from C-KS patients versus controls, except for AIDS-KS patients who showed a T-CD8+ expansion. However, a preferential infiltration of T-CD8+ cells was found in all KS lesions examined, which was maintained after culture of TIL in TCM. gamma IFN production was found in both PBMC and cultures derived from all KS examined; some IL-4 positive supernatants were found only in three AIDS-KS cases. Uninvolved skin did not show appreciable lymphocyte infiltration or cytokine production. The culture conditions of the lesional skin allowed also the appearance of adherent, spindle-like cells bearing markers of tissue macrophages. Finally, most or all of the PBMC, lesions, and macrophagic cell cultures from the skin lesions were found to be positive for HHV-8 infection by nested polymerase chain reaction (PCR). These findings indicate that patients with KS express a Th1 phenotype with a prevalent gamma IFN production, likely accounted for by the local T-CD8+ infiltration. By analogy with other viral infections (i.e., Epstein-Barr virus), this suggests that in loco recruitment of lymphoid cells and the subsequent gamma IFN production may be in response to or elicited by HHV-8 that was found in both PBMC and macrophagic cell cultures from the lesions of the same patients.