Gamma-herpesviruses and cellular signaling in AIDS-associated malignancies

Abstract

gamma-Herpesviruses, Epstein-Barr virus (EBV/HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), are involved in human carcinogenesis, particularly in immunocompromised patients. Virus-associated malignancies are becoming of significant concern for the mortality of long-lived immunocompromised patients, and therefore, research of advanced strategies for AIDS-related malignancies is an important field in cancer chemotherapy. Detailed understanding of the EBV and KSHV lifecycle and related cancers at the molecular level is required for novel strategies of molecular-targeted cancer chemotherapy. The present review gives a simple outline of the functional interactions between KSHV- and EBV-viral gene products and host cell deregulated signaling pathways as possible targets of chemotherapy against AIDS-related malignancies.

Figure 1

Schematic drawing of the organization of Epstein–Barr virus (EBV) and Kaposi's sarcoma‐associated herpesvirus (KSHV) linear genomes. Each viral gene‐coding region is flanked by multiple terminal repeat (TR) units. Different viral transcription patterns are observed in each latency types I, II, and III, and different EBNA are encoded by individual mRNA generated by different splicing of the long transcript. The open reading frames and latent replication origins discussed here are indicated., LMP, latent membrane protein.

Figure 2

Cell cycle regulatory proteins and viral gene products. Kaposi's sarcoma‐associated herpesvirus (KSHV) latent antigen LANA‐1 inactivates RB and p53, and KSHV k‐cyclin/CDK complex inactivates Cdk‐inhibitors and RB by phosphorylation (P). These viral product expressions promote G1‐S progression of the host cell. Viral products are indicated by red font.

Figure 3

Cell signaling manipulated by Epstein–Barr virus (EBV) and Kaposi's sarcoma‐associated herpesvirus (KSHV) viral products. (a) Latent phase. KSHV latent antigen LANA‐1, vFLIP and EBV non‐coding‐RNA EBER are expressed in latently infected cells. EBV latent membrane protein (LMP)2A and LMP1 are expressed in type II and III latency. (b) Lytic phase. The KSHV G‐protein coupled receptor (vGPCR), K15, and K1 induce multiple signals. The tyrosine residues (Y) in the cytoplasmic tails of K15 and K1 mediate signal initiation. Complex cell signaling manipulated by viral products is an advantage to virus‐infected cell survival. Viral products are indicated by red font.

Figure 4

Epstein–Barr virus (EBV) EBNA2 and Kaposi's sarcoma‐associated herpesvirus (KSHV) RTA promote Notch‐signaling. Ligand‐receptor interaction initiate Notch signaling, and Notch receptor cleaved product, Notch intracellular domain (NICD) activates CSL‐initiated transcription of target genes by recruiting transcriptional co‐activators. Expression of EBNA2 induces ligand‐independent CSL activation, and RTA expression activates Notch‐signaling by stimulation of CSL DNA‐binding. Although RTA causes reactivation of the KSHV lytic cycle, and both EBNA2 and RTA promote Notch‐signaling, EBNA2 does not reactivate the KSHV lytic cycle. Viral products are indicated by red font.

Figure 5

Anti‐apoptotic effects by viral products. Epstein–Barr virus (EBV) BHRF1 and Kaposi's sarcoma‐associated herpesvirus (KSHV) vBcl‐2 are functionally related to host cell anti‐apoptotic Bcl‐2 family containing Bcl‐2‐homology region 1–4 (BH1‐4). KSHV vIAP bridges active caspase‐3 (CASP‐3) and host cell Bcl‐2 through baculovirus IAP repeat domain (N‐BIR) to inhibit apoptosis‐execution by caspase‐3. Latent antigens, EBV EBNA1 and KSHV LANA‐1 suppress p53 activity and prevent p53‐induced apoptosis execution. Viral products are indicated by red font.