Identification of an HLA  A*0201–restricted CD8+T-cell epitope for the glycoprotein B homolog of human herpesvirus 8

Abstract

IntroductionHuman herpesvirus 8 (HHV-8; also termed Kaposi sarcomaassociated herpesvirus) is a gammaherpesvirus that is considered to be the causative agent of Kaposi sarcoma (KS), body cavity B-cell lymphoma, and multicentric Castleman disease. 1 T-cell immunity is thought to play an important role in control of HHV-8 infection and these associated diseases. [2][3][4][5] In this regard, we 2,3 and others 4 have demonstrated that major histocompatibility complex (MHC) class I-restricted, CD8 ϩ cytotoxic T lymphocytes (CTLs), and interferon ␥ (IFN-␥) responses are detectable in peripheral blood mononuclear cells (PBMCs) of HHV-8 ϩ individuals using recombinant vaccinia viruses expressing HHV-8 lytic and latent cycle proteins. These anti-HHV-8 T-cell responses are lower during human immunodeficiency virus type 1 (HIV-1) infection and may be involved in prevention of KS and other HHV-8-associated diseases.Support for the potential role of CD8 ϩ T-cell immunity in control of HHV-8 infection comes from several studies on immune control of acute and persistent infections with 2 other gammaherpesviruses, specifically, Epstein-Barr virus (EBV) and murine herpesvirus 68 (MHV-68). 6-10 Although EBV latency proteins can induce strong CD8 ϩ T-cell responses, 11 lytic cycle proteins are considered as major CD8 ϩ T-cell targets in both acute and persistent EBV infections. 12 Immunodominant epitopes restricted to different HLA class I alleles, which are important for our understanding of viral immunopathogenesis and development of appropriate vaccines, 13 have been determined for peptides derived from EBV structural proteins gp350 and gp85, and immediate-early (IE) and early proteins such as BZLF1, BRLF1, and BMLF1. [6][7][8][9] Compared to latency proteins, the frequency of CD8 ϩ T lymphocytes specific for peptides derived from lytic cycle proteins is higher in PBMCs of healthy virus carriers. 14 CD8 ϩ CTLs have also been demonstrated to secrete IFN-␥ in response to EBV lytic cycle antigens in seropositive individuals. 15 During primary EBV infectious mononucleosis, up to 60% of CD8 ϩ T cells circulating in blood are EBV-specific. 16 Furthermore, by use of a peptide-tetramer complex, Tan et al 17 have directly visualized from 0.5% to 6.6% of CD8 ϩ T blood cells in virus carriers that are specific for a single BMLF-1 epitope.In MHV-68 infection, lytic cycle proteins also induce CD8 ϩ T cell responses. 10,18,19 T cells specific for peptides derived from lytic cycle proteins dominate the acute phase of MHV-68 infection. 10,19 Moreover, vaccination with immunodominant CD8 ϩ T-cell epitopes derived from lytic cycle proteins of MHV-68 significantly reduces viral titers and the level of infected cells during acute infection. 20 We have tested CD8 ϩ T-cell reactivity to peptides derived from 5 HHV-8 lytic cycle proteins based on a prediction model for the HLA A*0201 motif in HHV-8-infected subjects to determine immunodominant epitopes to the virus. We chose HLA A*0201 because it is prevalent in a large percentage of the white populat...

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…KSHV expresses proteins that affect antigen presentation, B cell targeting, MHC class I display, and neutrophil and basophil activation. The KSHV-infected cell presents antigenic peptides from the virus in complex with MHC class I to cytotoxic T lymphocytes (CTLs) (64)(65)(66). Additionally, KSHV-infected B cells stimulate activation-induced cytidine deaminase (AID) expression and are targeted for elimination by NK cells through upregulation of NKG2D ligands (67).…”

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).…”

“…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.…”

Identification of an HLA-A*0201–restricted CD8+ T-cell epitope SSp-1 of SARS-CoV spike protein

“…[36][37][38] Antigen-specific T-cell responses from peripheral blood mononuclear cells (PBMCs) can be elicited with antigenic peptide-or protein-pulsed autologous DCs. 25,[39][40][41][42][43] Here, PBMCs were isolated from whole blood of 11 healthy HLA-A2.1 ϩ volunteer donors by Ficoll/Hypaque (Sigma) density gradient centrifugation. Human peripheral blood monocyte-derived DCs were generated as previously described by us.…”