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Kaposi sarcoma-associated herpesvirus (KSHV) is a B-lymphotropic virus whose primary site of replication is the oropharynx. KSHV can infect both T and B cells from primary tonsillar explant cultures. However, T cells do not support lytic replication, while B cells spontaneously produce substantial amounts of infectious virus. Here, we provide evidence for a mechanism by which activated T cells may promote or stabilize latency of KSHV infection in B cells. When mixed cultures of B cells and activated T cells were exposed to KSHV, little spontaneous virus production was observed. Removing T cells from the mix or treating the mixed culture with immune suppressants enhanced virus production. Adding back activated T cells to purified infected B cells efficiently suppressed KSHV production, primarily due to CD4(+) T cells. This suppressive activity required T cell activation and direct cell-cell contact, but not prior exposure to KSHV antigen. Suppression was not MHC restricted and did not result in killing of the target cell. We therefore propose that oropharyngeal T cells activated by a variety of stimuli can recognize ligands on infected target B cells, leading to signaling events that prevent spontaneous lytic activation and promote latent infection in this compartment.

The linkage of Kaposi sarcoma (KS) to infection by a novel human herpesvirus (Kaposi sarcoma-associated herpesvirus [KSHV]) is one of the great successes of contemporary biomedical research and was achieved by using advanced genomic technologies in a manner informed by a nuanced understanding of epidemiology and clinical investigation. Ongoing efforts to understand the molecular mechanisms by which KSHV infection predisposes to KS continue to be powerfully influenced by insights emanating from the clinic. Here, recent developments in KS pathogenesis are reviewed, with particular emphasis on clinical, pathologic, and molecular observations that highlight the many differences between this process and tumorigenesis by other oncogenic viruses.

Little is known about the role of CD1d-restricted T cells in antiviral immune responses. Here we show that the lytic replication cycle of the Kaposi sarcoma-associated herpesvirus (KSHV) promotes downregulation of cell-surface CD1d. This is caused by expression of the 2 modulator of immune recognition (MIR) proteins of the virus, each of which promotes the loss of surface CD1d expression following transfection into uninfected cells. Inhibition of CD1d surface expression is due to ubiquitination of the CD1d alpha-chain on a unique lysine residue in its cytoplasmic tail, which triggers endocytosis. Unlike MIR-mediated MHC class I downregulation, however, CD1d downregulation does not appear to include accelerated lysosomal degradation. MIR2-induced downregulation of CD1d results in reduced activation of CD1d-restricted T cells in vitro. KSHV modulation of CD1d expression represents a strategy for viral evasion of innate host immune responses and implicates CD1d-restricted T cells as regulators of this viral infection.

Kaposi sarcoma-associated (KS-associated) herpesvirus (KSHV) infection is linked to the development of both KS and several lymphoproliferative diseases. In all cases, the resulting tumor cells predominantly display latent viral infection. KS tumorigenesis requires ongoing lytic viral replication as well, however, for reasons that are unclear but have been suggested to involve the production of angiogenic or mitogenic factors by lytically infected cells. Here we demonstrate that proliferating cells infected with KSHV in vitro display a marked propensity to segregate latent viral genomes, with only a variable but small subpopulation being capable of stable episome maintenance. Stable maintenance is not due to the enhanced production of viral or host trans-acting factors, but is associated with cis-acting, epigenetic changes in the viral chromosome. These results indicate that acquisition of stable KSHV latency is a multistep process that proceeds with varying degrees of efficiency in different cell types. They also suggest an additional role for lytic replication in sustaining KS tumorigenesis: namely, the recruitment of new cells to latency to replace those that have segregated the viral episome.

Kaposi's sarcoma-associated (KS-associated) herpesvirus (KSHV) is a B-lymphotropic agent linked to AIDS-related lymphoproliferative disorders and KS. We and others have earlier identified two viral genes, K3 and K5, that encode endoplasmic reticulum proteins that downregulate surface MHC-I chains by enhancing their endocytosis. Here we have examined the ability of these proteins to influence the disposition of other host surface proteins implicated in immune recognition and activation. We report that K5, but not K3, expression in BJAB cells dramatically reduces ICAM-1 and B7-2 surface expression; B7-1 expression is unaffected. This K5-induced reduction can be reversed by coexpression of a dominant negative mutant of dynamin, indicating that the loss of ICAM and B7-2 surface expression is due to their enhanced endocytosis. This downregulation is functionally significant, because K5-transfected B cells show substantial impairment in their ability to induce T cell activation. K5 is thus the first example of a viral modulator of immunological synapse formation and T cell costimulation. We propose that its expression reduces T cell responses to KSHV-infected B cells early in infection, thereby diminishing antiviral cytokine release and the production of stimulatory signals for CTL generation.