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Description

Human herpesvirus-8 (also known as Kaposi's sarcoma-associated herpesvirus, HHV-8, KSHV) is etiologically associated with all forms of Kaposi sarcoma (KS) including classic, endemic, transplant-related, and AIDS-related, as well as rare neoplastic disorders. It is a double stranded DNA virus with a large genome that encodes for over 87 open reading frames (ORFs) including genes necessary for capsid, tegument, envelope, DNA replication and regulatory proteins. HHV-8 undergoes a bi-phasic lifecycle and can persist indefinitely in the infected host in a latent form during which time only a small fraction of regulatory viral proteins is expressed. The most prominent protein expressed in latently infected cells is the ORF73 gene product known as the latency-associated nuclear antigen (LANA) that functions to ensure the maintenance of the viral genome by tethering the viral episomal DNA to host cell chromosomes. It is a multi-functional protein that plays a role in the replication and long-term persistence of the viral episomal genome in dividing cells. It binds to mitotic chromosomes via its N-terminal region and to a 16-bp imperfect palindrome within the origin of replication (oriP) located in the viral terminal repeat (TR) through its C-terminal. LANA consists of a serine- and proline-rich N-terminal domain with a nuclear localization signal (NLS), a chromatin-binding motif (CBM), and domains responsible for interaction with the transcription regulators, mSin3 complex and Sp1. The central domain contains several highly repetitive acidic regions that vary in length and are responsible for the size variation of LANA proteins from different HHV-8 isolates. The proline-rich C-terminal third domain contains another NLS and is responsible for LANA dimerization and binding to the terminal repeats (TR) of the viral genomic DNA. HHV-8 infected latent cells are reported to induce the secretion of glutamate and activation of metabotropic glutamate receptor 1 (mGluR1). Elevated secretion of glutamate and mGluR1 activation has been linked to increased proliferation of HHV-8 infected cells. Use of glutamate release inhibitor and mGluR1 antagonists are shown to block the proliferation of infected cells. (Ref.: Kumar, B., et al. (2019). J. Virol. 93(9), e01812-18, Gjyshi, O., et al. (2015). J. Virol. 89(15), 7874-7892, Veettil, MV., et al. (2014). PLoS Pathog 10(10), e1004389).