Human Herpesvirus 8 Infects and Replicates in Primary Cultures of Activated B Lymphocytes through DC-SIGN

Abstract

Human herpesvirus 8 (HHV-8We hypothesized that the lack of permissive infection of B cells and B-cell lines with HHV-8 in vitro is related to the differential expression of the appropriate virus entry receptors. Several proteins have been reported to serve as HHV-8 entry receptors (3,25,33). We have shown previously that DC-SIGN, a C-type lectin first identified on dendritic cells (DC) (18), is an entry receptor for HHV-8 on DC and macrophages in vitro (33). DC-SIGN and its isomer DC-SIGNR were initially shown to be restricted in expression in vivo to dermal and lymphatic DC, activated macrophages, and vascular endothelial cells (38,40,44). Recent studies from our laboratory and others have demonstrated that B lymphocytes from peripheral blood and tonsils express DC-SIGN and that this expression significantly increases after B-cell activation mediated by CD40 ligand (CD40L) and interleukin 4 (IL-4) (22,34). These data suggest that DC-SIGN may also serve as an entry receptor on activated B (aB) cells and that its lack of expression on resting B (rB) cells may explain why previous attempts to infect B cells with HHV-8 have been had limited success.In the present study, we show that activated blood and tonsillar B cells expressing DC-SIGN can be productively infected with HHV-8, as determined by an increase in the level of viral DNA, the expression of lytic and latency-associated viral proteins, and the production of infectious virus. HHV-8 infection could be blocked by the pretreatment of the B cells with anti-DC-SIGN monoclonal antibody (MAb). These results are the first evidence of a fully productive infection of B cells and confirm the role of DC-SIGN as an entry receptor for this virus. This model can provide insight into the life cycle of HHV-8 and a better understanding of its pathogenesis.

Kaposi Sarcoma-associated Herpesvirus Degrades Cellular Toll-Interleukin-1 Receptor Domain-containing Adaptor-inducing β-Interferon (TRIF)

“…At the same time, KSHVs have a segment genomic DNA and protein product (K8.1) that induce the production of IFNs (39,40). KSHV infects many cell types, including B lymphocytes and dendritic cells (41)(42)(43)(44). These cells express multiple TLRs, and dendritic cells are potent IFN producers.…”

Is murine gammaherpesvirus-68 (MHV-68) a suitable immunotoxicological model for examining immunomodulatory drug-associated viral recrudescence?

“…Unlike EBV, the latency program of KSHV displays no obvious phenotype and the virus has neither been shown to immortalize nor transform primary B-lymphocytes (Ganem, 2010;Kliche et al, 1998;Rappocciolo et al, 2008). KSHV latency has been studied in cell culture and is similar to EBV in that latency is the default pathway for virus infection (Ganem, 2010).…”

“…Acute infections are mostly asymptomatic, but those who develop KS are usually immunosuppressed due to co-infection with HIV (Ganem, 2010;Kliche et al, 1998;Rappocciolo et al, 2008). Evidence exists for KSHV infection of endothelial cells, primarily from the isolation of KSHV DNA from KS spindle cells and in cells lining KS lesions (Ganem, 2010).…”

Role of RRV ORF52 in Virion Maturation

“…For KSHV, cellular receptors include ephrin A2 (EphA2), heparin sulfate, integrins -specifically α3β1, αvβ5, α8β1, and αIIbvβ3, the cysteine/glutamate transporter (xCT), and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) ( (6,122,135,148,161,252,257,258) and reviewed in (48)). RRV gB shares sequence homology to its homolog in KSHV, but, in contrast, to KSHV, RRV gB does not engage with integrins α3β1 or αvβ5 and does not have identified receptor(s) for mediating entry (107) and reviewed in (352)).…”

“…Kaposi's sarcomaassociated herpesvirus (KSHV) is a γ2 herpesvirus and the causative agent of Kaposi's sarcoma (KS), as well as two B-cell malignancies, multicentric Castleman's disease (MCD) (297) and primary effusion lymphoma (PEL) (reviewed in (46)). KSHV infects endothelial cells, but can also establish latency and replicate in T and B lymphocytes (123,206,220,221,257). …”