Kaposi’s sarcoma-associated herpesvirus （人疱疹病毒 8 型 ） In 1994, the Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) was identified as the etiologic agent （致病的相关因子 ） of Kaposi’s sarcoma (KS). which gene contributes to the initiation of KS ？
Latent genes are expressed in almost all spindle cells in late KS lesions Lytic genes are expressed during the phase of the viral life cycle when viral progeny are produced.these viral genes are expressed in cells ultimately destined to die (lyse)
KSHV vGPCR responsible for the initiation of KS evidence 1. when a KS model in which endothelial- specific retroviral transduction was used, vGPCR produced vascular tumors in mice 2. two transgenic animals that express vGPCR under either a ubiquitous (SV40) promoter or a T cell-specific promoter only manifest vascular tumors
The KSHV vGPCR is a member of the family of CXC chemokine G-protein- linked receptors.this receptor exhibits ligand-independent activities. activation of the serine-threonine kinase Akt by vGPCR may represent a critical intracellular pathway in the blockade of cell death
vGPCR induces the secretion of angiogenic growth factors from expressing cells, including VEGF, IL-8, and Gro- suggesting that vGPCR may serve a role both in direct cell transformation and indirect (paracrine) cell transformation
Mechanisms control vGPCR 1) vGPCR is transcribed within the 3' end of a bicistronic mRNA, thus restricting its expression 2) Host cytokines (e.g., SDF-1, IP-10) act as antagonists to vGPCR signaling
3) KSHV itself encodes a lytic gene, vMIP2, whose protein product acts as an antagonist to vGPCR signaling 4)As mentioned above, as a lytic gene, vGPCR is expressed in cells ultimately destined to die.
Proliferative signals initiated by vGPCR prolong lytic cell survival to ensure efficient viral replication. proangiogenic growth factors secreted by vGPCR-expressing cells recruit neighboring endothelial cells that are then infected by the newly formed progeny virion.
How can vGPCR be responsible for the initiation of KS tumors if its expression and signaling are so tightly controlled
under special circumstances (e.g., HIV co- infection, inflammation, aborted lytic cycle progression), dysregulation of the normal viral program may result in nonlytic expression and enhanced signaling of vGPCR, ultimately manifesting as KS.
1) HIV Tat increases expression of KSHV lytic genes, including vGPCR, whose expression is significantly enhanced in aggressive AIDS-KS as compared with the more benign classical KS lesions 2) Several inflammatory cytokines released by HIV infected cells can increase vGPCR signaling
The critical role for these locally released inflammatory cytokines for vGPCR oncogenesis was recently confirmed by a transgenic animal encoding a mutant vGPCR lacking a ligand binding domain that failed to manifest tumors despite its constitutive activity