T-cell immunity to herpesviruses in immune disorders

Abstract

Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) are wide-spread herpesviruses, which establish life-long persistence in the host upon primary infection. Primary infection with herpesviruses causes usually only mild symptoms, however in some situations, such as during immunosuppression or human immunodeficiency virus (HIV) infection, serious disease can develop. It is thought that these diseases are the consequence of deregulation of herpesvirus-specific T-cell immunity. To understand deregulation of herpesvirus-specific T-cell responses, we studied the kinetics of Epstein-Barr virus (EBV) and CMV-specific CD4+ and CD8+ T-cell responses during primary infection in patients developing IM or during chronic infection in various clinical settings, including patients with HIV infection and stem cell transplant (SCT) recipients. EBV-specific T-cell immunity is studied in patients with infectious mononuclosis. This study shows that T-cell responses are mainly directed to lytic proteins short after primary infection, whereas half a year after primary infection, most T-cell responses are directed to latent proteins. Furthermore, EBV-specific T-cell responses are studied in HIV infected individuals during HIV infection and after initiation of HAART. Previous data showed differences in kinetics of T-cell responses to either a latent (EBNA1) or a lytic (BZLF1) protein during HIV infection and long-term HAART. We now investigated whether the kinetics are representative for dynamics of responses to latent and lytic proteins in general or whether these responses are protein specific. To this end we determined T-cell responses to another latent and lytic protein. Our results suggest that the kinetics of T-cell responses to each protein are unique, rather than that they display a general pattern of latent or lytic T-cell responses. To determine whether CMV-specific T-cell responses can be restored after treatment with HAART, we aimed to study the matrix protein pp65 and immediate early antigen (IE)1-specific T-cell responses during HIV infection and treatment with HAART. This study suggests that HIV-infection leads to an altered CMV biology, affecting pp65- and IE1-specific T-cell responses in a different way, which is not restored by treatment with long-term HAART. Future studies should aim to achieve better insight in to EBV and CMV gene expression during HIV infection and treatment with HAART. It would be interesting to study viral gene expression in parallel with antigen-specific T-cell responses. In SCT patients we studied CMV-specific T-cell responses as well as T-cell activation, T-cell activation and perforin expression. We show that in patients with CMV reactivation CMV-specific IFN? production and proliferation were observed more frequently compared to patients without CMV reactivation. Furthermore a skewed phenotype towards more differentiated effector T cells was observed in patients with CMV reactivation. Also perforin expression by CD8+ T cells, which is a more general feature of cytolytic effector T cells, was higher in patients with CMV reactivation. Together these data may counter intuitively suggest that CMV antigen is required for CMV-specific T-cell reconstitution after SCT. We hypothesize that IE1-specific T-cell responses may be important against protection against disease in HIV infected individuals and SCT recipients. Therefore it would be interesting to study IE1-specific T-cell responses in HIV patients and SCT patients progressing towards CMV dis ease.