Reactivation and persistence of human herpesvirus-8 infection in B cells and monocytes by Th-1 cytokines increased in Kaposi's sarcoma

Patients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load higher than patients without KS and present a CD8(+) T-cell activation wit h production of Th1-type cytokines both in tissues and peripheral blood mon onuclear cells (PBMC). Because in tissues of KS patients detection of infla mmatory cytokines (IC) can precede detection of HHV-8 DNA and because signs of immunoactivation and/or dysregulation can precede KS development, we in vestigated the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell populations from 45 patients with KS and 45 patients at r isk of KS were analyzed for HHV-8 DNA and/or gene expression and for cell s urvival, growth, and phenotype before or after culture with or without the IC increased in KS. The results indicate that PBMC that are polymerase chai n reaction (PCR)-positive at day 0 generally loose the virus upon culture. However, the presence of IC maintains HHV-8 DNA load in cultured cells. In addition, IC increase viral load to detectable levels in PBMC from serologi cally positive patients that were PCR-negative before culture. gamma Interf eron is sufficient for these effects, whereas tumor necrosis factor and int erleukin-6 have little or no activity. The increase of HHV-8 DNA by IC is o bserved after short-term (7 days) or long-term (28 days) culture of the cel ls and occurs in one or both of the two circulating cell types that are inf ected in vivo: B cells and monocytes. In both cases it is associated with l ytic gene expression, suggesting that virus reactivation is one of the most likely mechanisms for the effect of IC on virus load. However, IC have als o effects on the cells target of HHV-8 infection, because they increase B-c ell survival and induce the growth and differentiation of monocytes into KS -like spindle cells with markers of endothelial macrophages. Because cells with markers of endothelial macrophages are present in blood and lesions fr om KS patients and are infected by HHV-8, these data may explain the high H HV-8 load associated with KS development and suggest that infected monocyte s may carry the virus to tissues, transmit the infection, or differentiate in loco in spindle cells with endothelial macrophage markers. (C) 1999 by T he American Society of Hematology.