FUNCTION OF DISINTEGRIN-LIKE DOMAIN OF KSHV gB IN REGULATING VIRUS INFECTION
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Date
2015-12-10
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Authors
Walker, Lia R.
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Publisher
East Carolina University
Abstract
KSHV, also referred to as human herpesvirus-8 (HHV-8), is the eighth and latest identified human herpesvirus. It is the causative agent for a variety of malignancies namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). The processes and mechanisms involved in virus entry are among the many intricacies not fully understood regarding KSHV and other viruses. As in other herpesviruses, KSHV target cell entry is a complex process consisting of multiple steps which include: initial attachment/binding to the cell, virus:cell surface receptor interactions, virus internalization/uptake, and subsequent trafficking of the virus for nuclear delivery. Viral envelope glycoproteins interact with target cell surface receptor molecules to facilitate entry into cells. For instance, virus envelope associated glycoprotein B (gB) of KSHV is known to interact with integrins via its RGD (Arg-Gly-Asp; 27-29aa) integrin binding domain. RGD of KSHV functionally interacts with integrins α3β1, αVβ3, and αVβ5 that have a role in initiating internalization. Cell surface receptors, like integrins, aid in a virus’ ability to establish a successful infection. In addition to RGD, KSHV gB also harbors the lesser studied integrin recognition motif, disintegrin-like domain (DLD; 66-85aa). As it pertains to virus entry in general, few studies have sought to establish a role for DLD, which is highly conserved among gB homologs. In the following studies, we employed phage display peptide library screening and recombinant viruses to determine that DLD of KSHV gB binds α9β1 integrin on the surface of target cells in an interaction critical for infection. We go on to specify a role for DLD-binding α9β1 in mediating KSHV entry by employing subcellular fractionation. The virus interactions with α9β1 are crucial for endosomal trafficking of KSHV, as integrin α9β1was observed to have a role in late endosomal escape of KSHV for cytosolic delivery. These studies provide new insights in regards to KSHV infectious entry into target cells. Advancing our knowledge of virus entry is critical for a thorough understanding of KSHV pathogenesis.