Date Published: January 16, 2010
Publisher: Hindawi Publishing Corporation
Author(s): Rebecca C. Robey, Salvinia Mletzko, Frances M. Gotch.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the aetiological agent of Kaposi’s sarcoma (KS), the most frequently arising malignancy in individuals with untreated HIV/AIDS. There are several lines of evidence to indicate that Kaposi’s sarcoma oncogenesis is associated with loss of T-cell-mediated control of KSHV-infected cells. KSHV can establish life-long asymptomatic infection in immune-competent individuals. However, when T-cell immune control declines, for example, through AIDS or treatment with immunosuppressive drugs, both the prevalence of KSHV infection and the incidence of KS in KSHV carriers dramatically increase. Moreover, a dramatic and spontaneous improvement in KS is frequently seen when immunity is restored, for example, through antiretroviral therapy or the cessation of iatrogenic drugs. In this paper we describe the current state of knowledge on the T-cell immune responses against KSHV.
Kaposi’s sarcoma-associated herpesvirus (KSHV) (or human herpesvirus 8 (HHV8)) is an oncogenic herpesvirus that is the aetiological agent of Kaposi’s sarcoma (KS), a mesenchymal tumour that is the most frequently arising cancer in individuals with untreated HIV/AIDs  and consequently one of the most common cancers in Sub-Saharan Africa . KSHV is also involved in the pathogenesis of at least two lymphoproliferative disorders—primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD).
Identifying the targets of the host’s cellular immune responses is important to our understanding of how KSHV infections are controlled in immunocompetent individuals and is a crucial step towards developing treatments such as immunotherapies, or even vaccines, against KSHV-related diseases.
The CD4 T-cell response against KSHV remains largely unexplored. Although some studies have looked at responses to KSHV by mixed CD8 and CD4 T-cell populations [10, 20, 38], there have been very few investigations specifically into the CD4 T-cell response against KSHV. One of the studies with mixed T cells reported that two samples out of 11 tested showed borderline CD4 T-cell reactivity . They did not state which of the two antigens they were testing (ORF57 (lytic) and ORF73 (latent)) initiated these CD4 responses. Another group reported the identification of two CD4 T-cell epitopes (the only ones described to date) from within the latent antigens K12 and K15 in one individual with AIDS-KS . In a few individuals, our group was able to detect CD4 responses to monocyte-derived dendritic cells lentivirally transduced to express KSHV antigens . These were less frequently detected than CD8 responses but appeared to preferentially target early and late lytic antigens. The longitudinal study of three iatrogenic KS patients described in the CD8 response section above reported the emergence of CD4 responses to K12 (latent) and K8.1 (late lytic), in conjunction with KS regression in two of these three individuals . The single individual in whom no KSHV-specific CD4 responses were observed was the only one out of the three that did not achieve full remission of their KS. The authors suggested that this was indicative of the importance of KSHV-specific CD4 responses in controlling KSHV infection. Although the small sample number and limited number of antigens make it difficult to reach a firm conclusion from this study, it seems likely that CD4 T cells may play a key role in the immune response against KSHV.
CD4 and CD8 T cells make up the majority of CD3 T cells found in the body and are both characterised by T-cell receptors comprised of an α-chain and a β-chain. A small proportion of CD3 T cells have T-cell receptors made up of a γ-chain and a δ-chain and are thus known as γδ T cells. γδ T cells typically account for less than five percent of circulating T cells, but are enriched in epithelial-rich tissues such as the skin and intestines . There are two main subtypes of γδ T cells, designated Vδ1 and Vδ2. In certain disease states, the representation of Vδ1 and Vδ2 shifts dramatically, for example in HIV-1 infection, Vδ2 cells are lost and Vδ1 cells expand [55, 56]. Although the significance of such changes is not understood, they imply a role for γδ T cells in antiviral immune responses .
There is still much to learn about the adaptive T-cell responses against KSHV, and the evidence examined above highlights the difficulty in detecting these weak responses as a major obstacle in the field, both in the work completed to date and for future investigations. Although some CD8 epitopes have been identified, it seems reasonable that there may be immunodominant epitopes yet to be determined. It is evident that the targets of the KSHV-specific CD4 response remain poorly understood. Further characterisation of the functionality and differentiation phenotypes of both CD8 and CD4 KSHV-specific T cells will be greatly aided by first achieving a better understanding of the targets of these cells. Such future investigations may assist the design of targeted therapeutic strategies to restore KSHV-specific T cell function, thus controlling KSHV infection in both AIDS and transplant recipients.