Identification of cytotoxic T lymphocyte epitopes of human herpesvirus 8

Abstract

SUMMARYThe human herpesvirus 8 (HHV-8) is a human c2-herpesvirus that is implicated in the development of Kaposi's sarcoma (KS), primary effusion lymphoma and Castelman's disease. Since the responses of cytotoxic T lymphocytes (CTL) play a key role in the control of herpesvirus infection, it is important to identify and to characterize the CTL target epitopes of HHV-8 viral antigens. In this study, using peptide-binding motifs, we selected potential human leucocyte antigen (HLA)-A2-binding peptides from kaposin A and glycoprotein H (gH), that are latent and lytic HHV-8 antigens, respectively. HLA-A2-binding peptides were tested for their capacity to induce CTL responses in HHV-8-negative healthy donors. By this approach, we found that the majority of individuals responded to two HHV-8-derived CTL epitopes, namely, VLLNGWRWRL (amino acids 16-25), which derives from kaposin A, and FLNWQNLLNV (amino acids 59-68), which derives from gH. In addition, memory CTL responses to these epitopes were detected in disease-free individuals infected by HHV-8 demonstrating that the two epitopes are relevant targets of CTL-mediated immunity in vivo. The identified epitopes may be investigated for the development of immunotherapeutic strategies against HHV-8-associated malignancies.

Clinical and pathological characteristics of HIV- and HHV-8–negative Castleman disease

“…B cells are known to play an essential role in HHV-8-positive MCD, in which B-cell depletion with rituximab is highly effective. 27 Furthermore, T-cell levels are correlated with HHV-8 viral loads in peripheral blood, 28 and polyfunctional effector memory HHV-8-specific CD8…”

Identification of CD8+ T Cell Epitopes within Lytic Antigens of Human Herpes Virus 8

“…The presence of CTL responses against both latent and lytic HHV-8 proteins has recently been characterized (8 -11) but, thus far, only a few immunogenic CTL epitopes have been identified within these Ags (12)(13)(14)(15)(16). At present, the role the identified epitope-specific CTL responses play in control of HHV-8-infected cells or HHV-8-positive tumors is not known.…”

Kaposi's Sarcoma-Associated Herpesvirus Cytotoxic T Lymphocytes Recognize and Target Darwinian Positively Selected Autologous K1 Epitopes

“…Kaposi's sarcoma-associated herpesvirus (KSHV) can establish chronic infections, as can other herpesviruses, such as Epstein-Barr virus (EBV), varicella-zoster virus, and cytomegalovirus (26). CTLs against KSHV proteins in HIV-1-positive (22) and HIV-1-negative (32) individuals have been demonstrated; however, there are only four MHC class I-restricted epitopes in KSHV that have been identified thus far (1,20,31,33).The KSHV K1 open reading frame (ORF-K1) encodes a 46-kDa transmembrane glycoprotein that has been shown to induce foci of transformation in rat fibroblasts (14), enhance KSHV lytic replication (12), cooperate in NF-B signaling in vitro (27) and in vivo (25), and potentially maintain latent infection by blocking B-cell activation and therefore the induction of lytic replication (13). ORF-K1, located at the extreme left-hand end of the KSHV genome, has positional homology with the gene encoding transforming protein LMP-1 of EBV.…”

“…Kaposi's sarcoma-associated herpesvirus (KSHV) can establish chronic infections, as can other herpesviruses, such as Epstein-Barr virus (EBV), varicella-zoster virus, and cytomegalovirus (26). CTLs against KSHV proteins in HIV-1-positive (22) and HIV-1-negative (32) individuals have been demonstrated; however, there are only four MHC class I-restricted epitopes in KSHV that have been identified thus far (1,20,31,33).…”