Differential regulation of the attachment of Kaposi's sarcoma-associated herpesvirus (KSHV)-infected human B cells to extracellular matrix by KSHV-encoded gB and cellular alphaV integrins.

Kaposi's sarcoma-associated herpesvirus (KSHV) has two modes of replications: latent and lytic replications. Reactivation from latency is dictated, in part, by the cell cycle. Herein, we have attempted to delineate the importance of cell cycle in KSHV pathogenesis by exploring the expression pattern of cell-surface receptors during different phases of the cell cycle. alphaV integrin expression is augmented during S phase in fibroblasts, epithelial and KSHV-infected cells. Using a Matrigel system, we pioneer the concept that KSHV-infected primary effusion lymphoma cells can attach to extracellular matrix proteins. This attachment is mediated primarily via alphaV integrins or virally encoded gB, and occurs preferentially in cells from S phase or cells from S phase actively supporting a lytic infection respectively. Such an ability of infected B cells to attach to endothelial cells may also aid in the dissemination of infection. The keystone of this work is that for the first time, we describe the ability of KSHV-infected B cells to preferentially use cellular (alphaV) or viral (gB) receptors to specifically bind cells, depending upon the stage of the cell cycle and infection.

Changes occurring on the cell surface during KSHV reactivation.

Following an infection, Kaposi's sarcoma-associated herpes virus (KSHV) exists predominantly in its latent state, with only 1-2% of infected cells undergoing lytic reactivation. We have previously demonstrated along with others a relationship between lytic reactivation and cell cycle progression (Bryan et al., 2006. J. Gen. Virol. 87: 519; McAllister et al., 2005. J. Virol. 79: 2626). Infected cells in the S phase are much more likely to undergo lytic reactivation when compared to those in G(0)/G(1) phase. Through the use of scanning electron microscopy (SEM), we analyzed changes occurring on the surface of cells undergoing KSHV reactivation. KSHV reactivation was observed predominantly in cells with smoother surface topology; a hallmark of cells derived from S phase. Interestingly, during the late stages of the reactivation process, we observed KSHV particles to egress cells through budding. Taken together, based on scanning electron microscopy and transmission electron microscopy evidences, we demonstrate for the first time the existence of a direct link between cell surface topology, cell cycle progression and KSHV reactivation.