Distinct expression of Kaposi’s sarcoma‐associated herpesvirus‐encoded proteins in Kaposi’s sarcoma and multicentric Castleman’s disease

Abstract

The expression of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)-encoded proteins is herein demonstrated in Kaposi's sarcoma (KS) and multicentric Castleman's disease (MCD) in a single lymph node derived from a patient with acquired immunodeficiency syndrome. Immunohistochemistry revealed that both lytic and latent KSHV proteins were expressed in cells of the MCD lesion. KSHV-encoded viral interleukin-6 was also detected in follicular dendritic cells of the germinal center. Cytoplasmic localization of open reading frame 59 protein and latency-associated nuclear antigen suggested KSHV activation in the MCD lesion. Moreover, a high copy number of KSHV was detected in the blood. Clinically, pegylated-liposomal doxorubicin induced regression of not only KS, but also lymphadenopathy of the MCD lesion with a decrease in KSHV load and human interleukin-6 in the blood. To the best of the authors' knowledge this is the first case demonstrating differential expression of virus proteins in two KSHV-associated diseases, KS and MCD, in the same section. The case confirms lytic KSHV infection in MCD, and suggests that clinical symptoms of MCD might be closely linked with KSHV activation.

Full-Length Isoforms of Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Accumulate in the Cytoplasm of Cells Undergoing the Lytic Cycle of Replication

“…These phenotypes were observed in cells infected with two strains of KSHV: BCBL-1-derived wild-type virus and recombinant rKSHV.219. We have also confirmed previous reports of cytoplasmic LANA expression in immunoblast-like cells in KSHV-associated MCD lesions (38,68). MCD lesions have a strong lytic character with a high percentage of infected cells expressing early-, intermediate-, and late-stage KSHV proteins, including ORF59, K2 (vIL-6), K8 (K-bZip), K9 (vIRF-1), K10 (vIRF-4), and the K8.1 glycoprotein (30,31,38,39), thus further correlating cytoplasmic LANA expression and KSHV lytic replication.…”

“…We have also confirmed previous reports of cytoplasmic LANA expression in immunoblast-like cells in KSHV-associated MCD lesions (38,68). MCD lesions have a strong lytic character with a high percentage of infected cells expressing early-, intermediate-, and late-stage KSHV proteins, including ORF59, K2 (vIL-6), K8 (K-bZip), K9 (vIRF-1), K10 (vIRF-4), and the K8.1 glycoprotein (30,31,38,39), thus further correlating cytoplasmic LANA expression and KSHV lytic replication. We attempted to show colocalization of nuclear ORF59 and cytoplasmic LANA in MCD lesions but were unsuccessful in developing techniques for simultaneous retrieval of both LANA and ORF59 antigens in paraffin-embedded MCD lesions.…”

“…One pattern was similar to that seen in spindled tumor cells in KS lesions with the presence of multiple punctate dots in the nucleus. The other pattern showed diffuse staining in both the cytoplasm and nucleus (38,68). To confirm this differential localization, we prepared paraffin-embedded sections from a KS skin nodule and two MCD lymph nodes for KSHV LANA localization using monoclonal antibody LN53 (73).…”

“…In contrast to the latency observed in KS lesions and PEL tumors, KSHV-associated MCD lesions show a high percentage of infected cells expressing early-, intermediate-, and late-stage KSHV proteins, including ORF59, K2 (vIL-6), K8 (K-bZip), K9 (vIRF-1), K10 (vIRF-4), and the K8.1 glycoprotein (30,31,38,39). The elevated expression of KSHV lytic genes suggests that MCD lesions are sites of lytic replication where differentiation signals in a unique B cell subset activate the lytic program of KSHV transcription.…”

“…In early immunohistochemical studies, LANA staining was detected in the cytoplasm of a subset of cells in MCD lesions (38,68). Subsequently, isoforms of LANA were detected in cytoplasmic extracts of KSHV-infected HEK293 and BCBL-1 PEL cells (65,69).…”