Human Herpesvirus 8 Interaction with Target Cells Involves Heparan Sulfate

Abstract

Human herpesvirus 8 (HHV-8) or Kaposi's sarcoma associated herpesvirus (KSHV) is associated with Kaposi's sarcoma and primary effusion lymphoma. In vivo, HHV-8 DNA and transcripts have been detected in B cells, endothelial cells, macrophages, and epithelial cells. HHV-8 infects a variety of cell lines of human and animal origin, leading to latent or abortive infection. This study shows that the broad cellular tropism of HHV-8 may be in part due to its interaction with the ubiquitous host cell surface molecule, heparan sulfate (HS). This conclusion is based on the following findings: (i) HHV-8 infection of human foreskin fibroblast (HFF) cells was inhibited in a dose-dependent manner by soluble heparin, a glycosaminoglycan closely related to HS. Chondroitin sulfates A and C did not inhibit HHV-8 infection. (ii) Enzymatic removal of HFF cell surface HS with heparinase I and III reduced HHV-8 infection. (iii) Soluble heparin inhibited the binding of radiolabeled HHV-8 to human B cell lines, embryonic kidney epithelial (293) cells, and HFF cells, suggesting interference at the virus attachment stage. (iv) Cell surface adsorbed HHV-8 was displaced by soluble heparin. (v) Radiolabeled HHV-8 also bound to wild-type HS expressing Chinese hamster ovary (CHO-K1) cells. In contrast, binding of virus to mutant CHO cells deficient in HS was significantly reduced. These data show that the gamma2 herpesvirus HHV-8, similar to some members of alpha, beta, and gamma2 herpesviruses, adsorbs to cells by binding to cell surface HS-like moieties. Heparin did not completely prevent the binding and infectivity of HHV-8, suggesting that HHV-8 interactions with HS could be the first set of ligand-receptor interaction leading to the binding with one or more host cell receptors essential for the subsequent viral entry process.

The Kaposi's sarcoma-associated herpesvirus complement control protein (KCP) binds to heparin and cell surfaces via positively charged amino acids in CCP1–2

“…KCP did not bind to pgsA-745 cells, which strongly suggests that glycosaminoglycans are the compound that KCP interacts with on the CHO cells. This finding is interesting, given the fact that KSHV binds to heparan sulfate during its attachment to its target cells (Akula et al, 2001b;Birkmann et al, 2001). So far, gpK8.1 and gB have been identified as the heparan sulfate binding ligands on KSHV (Akula et al, 2001a;Birkmann et al, 2001;Wang et al, 2001).…”

Kaposi's Sarcoma-Associated Herpesvirus Glycoprotein K8.1 Is Dispensable for Virus Entry

“…Herpes simplex virus, human cytomegalovirus, and EpsteinBarr virus (EBV) have been shown to enter cells by either pH-independent or pH-dependent pathways, depending on the cell type (8,13,30,37,41,47,51). KSHV has been shown to enter certain cells (human foreskin fibroblast cells and B cells) by endocytosis (1,4). Regardless of the mode of virus entry, the release of capsids into the cytoplasm is thought to involve fusion of the viral envelope with either plasma or endosomal membranes.…”

“…In addition, the K1, K8.1, and vOX2 (K14) glycoproteins are unique to KSHV, with no counterparts in other herpesviruses (10,11,36,49). KSHV gB and glycoprotein K8.1A mediate the initial binding of virions to glycosaminoglycans, e.g., heparan sulfate on cell surfaces (2,4,7,57). In agreement with the strong binding of purified K8.1A to heparan sulfate moieties on cell surfaces, initial studies showed that a soluble form of K8.1A inhibited KSHV attachment to cells (57).…”

“…Virus penetration is achieved by means of either direct fusion of viral envelopes with cellular membranes or virion endocytosis and subsequent fusion of viral envelopes with endosomal membranes, releasing capsids into the cytoplasm of infected cells. For KSHV, initial attachment to cell surfaces is mediated by the binding of gB and glycoprotein K8.1 to heparan sulfate moieties (2,4,7,57). In addition, gB binds to the ␣ 3 ␤ 1 -integrin receptor, which is thought to facilitate virus penetration into certain cells by means of endocytosis (3).…”

Herpesvirus saimiri-based vector biodistribution using noninvasive optical imaging

“…It is generally accepted that 10 6 cells need to express luciferase before detection can be achieved, 38 in addition to which the heart is shielded by the ribcage which may reduce detectable light compared to the lower abdomen. Heparan sulphate has been identified as the cell surface receptor for the HVS homologue human herpesvirus-8, 39 and it is likely that HVS shares the same receptor. Therefore, the infection of different tissues within the mouse following i.v.…”