Interaction of KSHV with Host Cell Surface Receptors and Cell Entry

Abstract

Virus entry is a complex process characterized by a sequence of events. Since the discovery of KSHV in 1994, tremendous progress has been made in our understanding of KSHV entry into its in vitro target cells. KSHV entry is a complex multistep process involving viral envelope glycoproteins and several cell surface molecules that is utilized by KSHV for its attachment and entry. KSHV has a broad cell tropism and the attachment and receptor engagement on target cells have an important role in determining the cell type-specific mode of entry. KSHV utilizes heparan sulfate, integrins and EphrinA2 molecules as receptors which results in the activation of host cell pre-existing signal pathways that facilitate the subsequent cascade of events resulting in the rapid entry of virus particles, trafficking towards the nucleus followed by viral and host gene expression. KSHV enters human fibroblast cells by dynamin dependant clathrin mediated endocytosis and by dynamin independent macropinocytosis in dermal endothelial cells. Once internalized into endosomes, fusion of the viral envelope with the endosomal membranes in an acidification dependent manner results in the release of capsids which subsequently reaches the nuclear pore vicinity leading to the delivery of viral DNA into the nucleus. In this review, we discuss the principal mechanisms that enable KSHV to interact with the host cell surface receptors as well as the mechanisms that are required to modulate cell signaling machinery for a successful entry.

ESCRT-0 Component Hrs Promotes Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus in Human Dermal Microvascular Endothelial Cells

“…7C). Phosphorylation of these proteins orchestrates membrane organization and dynamics through remodeling of cytoskeleton and thus facilitates the entry by macropinocytosis (8)(9)(10). Previous studies have reported that during macropinocytosis, PI3-K binds to ␣-actinin-4, forms an actinin-4 -F-actin network surrounding macropinosomes, and regulates the morphological changes associated with macropinosome formation (39,50).…”

“…The interaction of KSHV with its specific entry receptors leads to the formation of a multimolecular receptor complex consisting of integrins, xCT, and EphA2 (2,4,7). Receptor engagement and multimolecular receptor complex formation result in autophosphorylation of focal adhesion kinase (FAK) and activation of Src, phosphatidylinositol 3-kinase (PI3-K), and Rho GTPases, and all of these molecules are targeted to specific entry sites on the plasma membrane (8)(9)(10). Our previous studies have demonstrated that the signal transduction pathways induced by KSHV and the consequent activation of their downstream molecules play a central role in coordinating the actin dynamics and the membrane protein assembly required for the successful entry of the virus into the cytoplasm (8)(9)(10).…”

“…Receptor engagement and multimolecular receptor complex formation result in autophosphorylation of focal adhesion kinase (FAK) and activation of Src, phosphatidylinositol 3-kinase (PI3-K), and Rho GTPases, and all of these molecules are targeted to specific entry sites on the plasma membrane (8)(9)(10). Our previous studies have demonstrated that the signal transduction pathways induced by KSHV and the consequent activation of their downstream molecules play a central role in coordinating the actin dynamics and the membrane protein assembly required for the successful entry of the virus into the cytoplasm (8)(9)(10). The endocytosed viral particles are then transported toward the nuclear periphery along the microtubules by utilizing dynein motor proteins to deliver their DNA content into the nucleus (11).…”

Extracellular vesicles: novel vehicles in herpesvirus infection

“…Indeed, due to the complexity of viral attachment and entry, KSHV enters cells by dynamin-dependent clathrin-mediated endocytosis and dynamin-independent micropinocytosis. It was revealed that irregular cup-shaped endocytic vesicles are required for successful infection (Veettil et al, 2014). However, no other prominent study on exosomes related to KSHV has been published to date.…”

Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis

“…Changes in levels of various host cell-signaling proteins, which are known to play an important role in KS pathogenesis, were evaluated. These host cell signaling proteins are involved in entry, pathogenesis, and latency establishment of KSHV, with FAK, Src, and AKT phosphorylation being essential for KSHV entry (11,31). ERK and AKT promote infection and increase survival of the infected cells (32,33).…”