Identification of Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Specific Cytotoxic T-Lymphocyte Epitopes and Evaluation of Reconstitution of KSHV-Specific Responses in Human Immunodeficiency Virus Type 1-Infected Patients Receiving Highly Active Antiretroviral Therapy

Abstract

Following the introduction of highly active antiretroviral therapy (HAART), the incidence of Kaposi's sarcoma (KS) has significantly declined in human immunodeficiency virus type 1 (HIV-1)-positive (HIV-1 ؉ ) individuals and clinical remission is often observed. We hypothesize that these effects are partly due to anti-KS-associated herpesvirus (KSHV) immune restoration. Here, 15-mer overlapping peptides from proteins K12 and K8.1 were used to identify novel KSHV-specific cytotoxic T-lymphocyte epitopes. Three immunogenic peptides, two lytic and one latent, were subsequently used to monitor the anti-KSHV CD8 ؉ T-cell responses in a cohort of 19 HIV-1 ؉ KSHV ؉/؊ KS ؉/؊ individuals during 52 weeks of HAART. KSHV and HIV-1 loads, KSHV antibody titers, and both CD4 ؉ and CD8 ؉ T-lymphocyte counts were enumerated. Prior to HAART, the total number of spot-forming cells (SFC) for all three peptides correlated with both CD4؉ and CD8 ؉ T-lymphocyte counts (P < 0.05) in the KSHV-positive KS-positive cohort (n ‫؍‬ 11). Following 52 weeks of HAART, significant decreases in HIV-1 and KSHV loads were associated with significant increases in CD4 ؉ T-lymphocyte counts and number of SFC for the three KSHV-specific peptides. Although these increases were modest in comparison to the number of SFC observed with the HIV-1 gag peptide SLYNTVATL, they represented a fourfold increase from the baseline, continuing an upward trend to week 52.

Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice

“…While cellular responses to KSHV infection have been studied, our understanding of antibody response to KSHV or in the context of KSHV infection is very limited. The general consensus is that KSHV-specific responses are frequent, diverse, and strongly differentiated toward an effector phenotype (CTLs) in patients who control the infection (42)(43)(44)(45)(46). Conversely, KSHV-specific CTLs are very rare in patients who progress to KS, supporting the crucial role of cellular immune responses in controlling KSHV replication, preventing malignancies and conferring resistance to persistent infection (42)(43)(44)46).…”

“…The general consensus is that KSHV-specific responses are frequent, diverse, and strongly differentiated toward an effector phenotype (CTLs) in patients who control the infection (42)(43)(44)(45)(46). Conversely, KSHV-specific CTLs are very rare in patients who progress to KS, supporting the crucial role of cellular immune responses in controlling KSHV replication, preventing malignancies and conferring resistance to persistent infection (42)(43)(44)46). Although in few cases of MCD polyfunctional KSHV-specific CD8 responses have been observed, suggesting that cellular immunity is less protective in MCD than in KS, a level of immune escape is present also in MCD but restricted to fully differentiated effector memory CD8 + T cells (47).…”

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.…”

γδ+ T Cells Involvement in Viral Immune Control of Chronic Human Herpesvirus 8 Infection

“…H uman herpesvirus 8 (HHV-8), 3 also known as Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of several infectious diseases including Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (1). Like other herpesviruses, HHV-8 is able to establish a predominantly latent, life-long infection in its host.…”

“…The increased incidence of these diseases in immunocompromised individuals suggests that host immune control may be essential in preventing HHV-8-associated diseases (2). Several studies have demonstrated the anti-HHV-8 specificity of TCR ␣␤ ϩ CD8 ϩ CTL (3)(4)(5)(6)(7)(8)(9)(10). HHV-8 specific CTL responses to latent and lytic viral proteins have been detected during primary HHV-8 infection (11).…”