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New viruses shake old paradigms
Chen-Yu Wang and Bill Sugden
McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, USA
Find articles by Wang, C. in: JCI | PubMed | Google Scholar
McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, USA
Find articles by Sugden, B. in: JCI | PubMed | Google Scholar
Published January 1, 2004 - More info
J Clin Invest. 2004;113(1):21–23. https://doi.org/10.1172/JCI20662.
© 2004 The American Society for Clinical Investigation
Tumor viruses cause at least 15% of human cancers. These oncogenic viruses have been identified by the retention of their genomes in precursors to tumor cells and in frank tumor cells. Two members of the herpesvirus family, Kaposi sarcoma–associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are human oncogenic viruses. Herpesviruses kill infected host cells during the production of progeny virus; the generation of virus would have to be avoided in order for infected cells to be sustained as tumors. KSHV and EBV cause several human lymphomas, and these tumor cells conform to our expectations: the tumor cells maintain the viral DNA extra-chromosomally, they express few viral genes, they rarely support virus production, and thus they are classified as being infected latently. However, KSHV-associated Kaposi sarcoma (KS), the cancer for which this virus is named, does not so obviously conform to our expectations. Instead, lytic replication of KSHV is usually found in some cells within KS lesions.
KS lesions contain both spindle-shaped endothelial cells that are latently infected with KSHV as well as cells that support the production of progeny virus. In this issue of the JCI, Grundhoff and Ganem document a striking feature of infection with KSHV, which may provide part of the reason for the lytic replication KSHV undergoes in some cells of KS lesions (1). The authors exposed multiple human and murine cell lines and a primary human endothelial cell strain to KSHV and showed that cells are infected via expression of latency-associated nuclear antigen 1 (known as LANA1), the viral protein that is required for viral DNA replication. They found that the infected, proliferating cells lost the virus within several days and up to 3 weeks after initial infection. The initially infected endothelial cells also rapidly lost their spindle shape. One cell line derived from KS and one fibroblast cell line maintained latent infections in approximately 10% of cells. The authors explored the mechanism of this general loss of the viral plasmid and infection by analyzing KSHV-infected cells. They also examined the fate of transfected plasmid replicons derived from KSHV, which contain the viral DNA replication origin (terminal repeat), with the expression of LANA1 in cis or in trans. Although these plasmids did replicate, they, like intact KSHV, were rapidly lost from most proliferating cells. These findings parallel those made with plasmid replicons derived from EBV (2), which are also initially rapidly lost from cells, although the plasmids themselves replicate. The traditional selection for plasmids that encode resistance to drugs has probably obscured this common, initial, rapid loss and explains our late recognition of this event.
Viruses such as KSHV and EBV, which maintain themselves extra-chromosomally in infected, proliferating cells, are lost from those cells unless they provide a selective growth or survival advantage. The work of Grundhoff and Ganem indicates that infection of multiple cell types generally leads to the loss of KSHV, showing that under these conditions KSHV fails to provide these proliferating cells with a selective advantage over uninfected cells (1). This observation may explain the difficulties researchers have had previously in documenting infection of cell lines with KSHV. In contrast, EBV can at least provide resting cells a selective advantage. Upon infecting primary B lymphocytes, EBV induces and maintains cell proliferation and is accordingly retained in the proliferating cells. The selective advantages that KSHV provides KS are now being assessed. Clearly, a fraction of two cell lines infected with KSHV retains the viral genome, indicating that in culture, KSHV does provide these cells with a selective advantage.
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A possible contribution of the lytic cycle to oncogenesis
Grundhoff and Ganem propose that the rapid loss of KSHV from infected cells that they have observed in vitro likely occurs in endothelial cells in vivo and may be one reason for the frequent productive infection observed in spindle cells within KS lesions: new viruses would be required to recruit newly infected cells to the lesion (1). This proposition is consistent with the recent work of Ciufo et al. (3), who have found that KSHV infection of primary dermal microvascular endothelial cells yielded mixtures of latently infected spindle-shaped cells and small populations of productively infected cells (3). The virus released by the latter population was able to infect freshly added endothelial cells in order to maintain the mixed infected population (Figure 1). Other features of productive infection are also likely to contribute to KS. Viral genes thought not to be expressed during latent infection, based on analyses of KSHV-positive lymphoma cells, may be pivotal for the proliferation of KSHV-infected endothelial cells. KSHV G protein–coupled receptor (vGPCR), which is expressed early in productive infection, is one such viral gene. By itself, vGPCR can immortalize human primary endothelial cells and induce KS-like lesions in a mouse (4, 5).
Figure 1A model to explain one potential role for productive infections by KSHV in KS lesions. (I) KSHV (shown as an enveloped iscosahedral core) can infect cuboidal endothelial cells and (II) induce a spindle-shaped morphology in these cells. These infected spindle-shaped cells can proliferate, lose KSHV rapidly, and (III) revert to uninfected, cuboidal cells. (IV) The spindle-shaped cells also can support production of KSHV. (V) The released KSHV can infect more cells, inducing the change to the spindle shape and maintenance of the infected lesion.
A traditional hallmark of herpesviruses has been their latent infection, a relationship between the virus and host cell in which infected cells survive and the virus persists with little expression of its genes and without the production of progeny virus. The generality of this paradigm may be waning as the relationships between new herpesviruses and host cells are elucidated. Analysis of KSHV infection of endothelial cells has indicated that these cells may transition readily from latent to productive infection and that these transitions likely contribute to the pathogenesis of KS.
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