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Comment
. 2011 Mar;121(3):838-41.
doi: 10.1172/JCI46499. Epub 2011 Feb 21.

Unraveling virus-induced lymphomagenesis

Chris Boshoff  1
Affiliations
Comment

Unraveling virus-induced lymphomagenesis

Chris Boshoff. J Clin Invest. 2011 Mar.

Abstract

Kaposi sarcoma herpesvirus (KSHV), a human gammaherpesvirus, is the etiological agent for the endothelial-derived Kaposi sarcoma (KS) and also for certain lymphoproliferative disorders. In these lymphoproliferations, the KSHV-infected cells carry the stigmata of B lymphocytes, with plasmablastic features. The JCI has published three manuscripts addressing key questions related to B cell infection and viral latent expression in B cells. Myoung and Ganem provide evidence that CD4(+) lymphocytes suppress KSHV replication, promoting latency in B cells; Hassman and colleagues show that KSHV infection drives plasmablast differentiation in a subset of IgM(+) λ light chain-expressing cells; and Ballon and colleagues describe the in vivo transdifferentiation of B lymphocytes by KSHV-encoded viral FLICE-inhibitory protein (vFLIP).

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Figures

Figure 1
Figure 1. Early events after EBV and KSHV infection of tonsillar cells.
(A) EBV is amplified by permissive epithelial cells (lytic infection) and infects mucosal naive B cells. The viral default pathway in B cells is latent infection, where EBV persists as an episome (red circle). A minority of infected B cells are transformed (TrB). In infectious mononucleosis, a significant expansion of transformed lymphoblastoid cells occurs. Anti-EBV antigen CD4+ and CD8+ T cells control the proliferation of transformed cells. EBV persists in B lymphocytes, as part of the long-lived memory B cell pool (MeB). (B) Early events during KSHV infection are less established. It is uncertain whether B cells become infected after amplification of KSHV in epithelium. Data presented in this issue suggest that KSHV induces significant spontaneous lytic replication ex vivo in tonsillar-derived B cells (2). This lytic infection is suppressed when infected B cells come in contact with activated CD4+ T cells. The suppression of spontaneous viral lytic cycle entry in B cells is MHC unrestricted and not dependent on killing of target cells. New data also suggest that the primary target for KSHV in tonsillar explants could be IgM+ memory B cells (3). The majority of KSHV latent infected B cells after exposure of tonsillar explants to virus express IgMλ. KSHV induces plasmablastic differentiation of these IgMλ+ cells. An enrichment of IgMλ-expressing plasmablasts also occurs in inducible vFLIP knockin mice, targeting vFLIP to different stages of B cell proliferation (4). Such IgMλ+ infected plasmablasts are thought to cause KSHV-related MCD. Lytic infected cells are indicated by disrupted nuclear membranes.
Figure 2
Figure 2. KSHV-related plasmablastic MCD.
(A) KSHV-LANA–positive cells are scattered throughout the mantle zone of a lymph node affected by MCD. (B) Higher magnification of MCD mantle zone. The KSHV-positive cells (black arrowheads) are large, have prominent nuclei with 1 or 2 nucleoli, and resemble plasmablastic cells. Lymphocytes surrounding the plasmablasts stain negative for KSHV. Reprinted with permission from ref. (copyright 1999, National Academy of Sciences, USA). Original magnification, ×140.
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References

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