Kaposi's sarcoma-associated herpesvirus immunoevasion and tumorigenesis: two sides of the same coin?

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) [or human herpesvirus 8 (HHV-8)] is the most frequent cause of malignancy among AIDS patients. KSHV and related herpesviruses have extensively pirated cellular cDNAs from the host genome, providing a unique opportunity to examine the range of viral mechanisms for controlling cell proliferation. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins target retinoblastoma protein and p53 control of tumor suppressor pathways, which also play key effector roles in intracellular immune responses. The immune evasion strategies employed by KSHV, by targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts.

Figure 1

Proliferative disorders associated with KSHV infection range from monoclonal neoplasia in primary effusion lymphoma (PEL) to multiclonal hyperplasia in multicentric Castleman’s disease (MCD). Kaposi’s sarcoma (KS) has both hyperplastic and neoplastic features. LANA1 immunostaining of (A) KS, (B) MCD, and (C ) PEL shows typical nuclear staining of virus-infected cells. vIL-6 expressed from (D) infected B cells in the germinal center mantle zone of MCD drives proliferation of uninfected cells.

Figure 2

The ~140-kb KSHV genome composed of a single long unique region with over 80 open reading frames (splice patterns not shown) flanked by G/C-rich terminal repeat units. Gene blocks containing well-conserved herpesviral genes (white) are separated by block of genes unique to KSHV and other rhadinoviruses (black). A full description of the KSHV genes is found in Reference 116. Gene names correspond to positional and sequence homologs found in HVS, which is the prototype rhadinovirus. Genes are numbered from left to right, from ORF4 to ORF75, with the first three homologs to HVS genes being absent or displaced from their corresponding positions in HVS. Genes unique to KSHV, including most of the cell regulatory homologs, are given a K prefix, e.g., ORF K1. Because several HVS genes are absent from the KSHV genome (e.g., ORF1), gene names are not necessarily consecutive.

Figure 3

The range of immune regulatory pathways in a B cell inhibited by specific KSHV immune evasive proteins. KSHV proteins that have been experimentally shown to induce cell transformation and proliferation include KIS, vIL-6, vFLIP, and vIRF1.

Figure 4

Autocrine mechanism of vIL-6 action to inhibit IFN-induced cell cycle arrest. The vIL-6 promoter is activated by IFN-α signaling, acting as a sensor of IFN signaling activity. vIL-6 directly activates the IL-6 gp130 signal transducer molecule, whereas hIL-6 requires gp80, but this is downregulated by IFN. Reprinted with permission (22).

Figure 5

Examples of immune activation of tumor suppressor checkpoints. Both cell cycle arrest and apoptosis can be initiated by immune recognition of a virus-infected cell. KSHV vIL-6, vIRF1, and vFLIP, which are putative oncogenes, inhibit these responses.

Figure 6

vCYC inhibits the pRB G1/S checkpoint by cyclin-dependent kinase phosphorylation and induces apoptosis when overexpressed alone. vCYC is resistant to cellular cyclin-dependent kinase inhibitors and may also act at additional points in the cell cycle. vCYC-induced apoptosis is p53 dependent but does not occur through E2F–p14ARF activation. KSHV inhibitors of p53, such as LANA1 and LANA2, are potential candidates to prevent vCYC-induced apoptosis during latent virus infection.