INTERACTION BETWEEN INFLAMMATORY CYTOKINES AND HHV-8 INFECTED MONOCYTES ARE KEY TO THE DEVELOPMENT OF KAPOSI'S SARCOMA (KS)

Abstract

66 Background. Patients with KS are characterized by a CD8+ T cell activation with production of Th1-type cytokines and a high HHV-8 load both in PBMC and tissues. KS lesions themselves are infiltrated by T cells (CD8+ and CD4+) and monocyte-macrophages producing inflammatory cytokines (IC) and, in particular, γIFN that, in turn, cooperates with other IC in promoting the formation of KS spindle cells with angiogenic phenotype (Sirianni et al, Blood, in press; Fiorelli et al, Blood, in press). This suggests that part of KS pathogenesis is related to the production of IC, perhaps as an immune response to HHV-8 infection. However, in early KS lesions and uninvolved tissues production of γIFN can precede the detection of HHV-8 DNA whose load increases with lesions progression. This suggests that IC may be responsible for this effect and activate HHV-8 infection. Methods. PBMC and purified cell populations from homosexual men with KS and AIDS, with AIDS, or asymptomatic were analyzed by PCR, RT-PCR and in situ hybridization (ISH) for HHV-8 DNA and gene expression after culture with or without the IC increased in KS. HHV-8 was transmitted to cultured PBMC and purified cell types. Immunocytochemistry and FACS analysis were performed to analyze the effect of IC on cell survival, growth and phenotype. Results. The same combination of IC increased in KS (γIFN, TNF, IL-1, GM-CSF, IL-6, oncostatin M) activates HHV-8 lytic infection in PBMC from homosexual men with AIDS-KS or AIDS and maintains or increases viral DNA in PBMC that, in the absence of IC, is lost upon culture. These effects are directed toward B cells and monocytes that are infected by HHV-8 in vivo. In addition, HHV-8 can be transmitted to B cells, T cells, monocytes-macrophages and monocyte-derived dendritic cells. In transmission experiments with PBMC, IC stimulate both HHV-8 lytic infection and the long-term maintenance of the virus, that is associated with induction of the latent T0.7 viral RNA. Finally, IC promote the development from monocytes of KS spindle cell progenitors bearing markers of endothelial macrophages. Since these cells are infected by HHV-8 and are also found in the lesions, this suggests that they may localize into tissues and contribute to multifocal lesion development. Conclusions. HHV-8 lytic and persistent infection is promoted in B cells, T cells, and monocyte-macrophages by the same IC increased in KS and in individuals at risk of KS. Since B cells are few or absent in KS lesions, whereas monocyte-macrophages and T cells are abundant, the data suggest that infected monocytes, T cells, and spindle cells progenitors may carry the virus to tissues, where HHV-8 may reactivate upon the action of the IC present in the lesions. Lytically infected monocytes may be a reservoir of virus for endothelial and spindle cells, which are latently infected. Thus, the interaction between IC and HHV-8 infected monocytes may be key to the development of KS in susceptible individuals.