Cross-sectional analysis of CD8 T cell immunity to human herpesvirus 6B

Human herpesvirus 6 (HHV-6) is prevalent in healthy persons, causes disease in immunosuppressed carriers, and may be involved in autoimmune disease. Cytotoxic CD8 T cells are probably important for effective control of infection. However, the HHV-6-specific CD8 T cell repertoire is largely uncharacterized. Therefore, we undertook a virus-wide analysis of CD8 T cell responses to HHV-6. We used a simple anchor motif-based algorithm (SAMBA) to identify 299 epitope candidates potentially presented by the HLA class I molecule B*08:01. Candidates were found in 77 of 98 unique HHV-6B proteins. From peptide-expanded T cell lines, we obtained CD8 T cell clones against 20 candidates. We tested whether T cell clones recognized HHV-6-infected cells. This was the case for 16 epitopes derived from 12 proteins from all phases of the viral replication cycle. Epitopes were enriched in certain amino acids flanking the peptide. Ex vivo analysis of eight healthy donors with HLA-peptide multimers showed that the strongest responses were directed against an epitope from IE-2, with a median frequency of 0.09% of CD8 T cells. Reconstitution of T cells specific for this and other HHV-6 epitopes was also observed after allogeneic hematopoietic stem cell transplantation. We conclude that HHV-6 induces CD8 T cell responses against multiple antigens of diverse functional classes. Most antigens against which CD8 T cells can be raised are presented by infected cells. Ex vivo multimer staining can directly identify HHV-6-specific T cells. These results will advance development of immune monitoring, adoptive T cell therapy, and vaccines.
Author summary This paper deals with the immune response to a very common virus, called human herpesvirus 6 (HHV-6). Most people catch HHV-6 in early childhood, which often leads to a disease known as three-day fever. Later in life, the virus stays in the body, and an active immune response is needed to prevent the virus from multiplying and causing damage. It is suspected that HHV-6 contributes to autoimmune diseases and chronic fatigue. Moreover, patients with severely weakened immune responses, for example after some forms of transplantation, clearly have difficulties controlling HHV-6, which puts them at risk of severe disease and shortens their survival. This can potentially be prevented by giving them HHV-6-specific "killer" CD8 T cells, which are cells of the immune system that destroy body cells harboring the virus. However, little is known so far about such T cells. Here, we describe 16 new structures that CD8 T cells can use to recognize and kill HHV-6-infected cells. We show that very different viral proteins can furnish such structures. We also observe that such T cells are regularly present in healthy people and in transplant patients who control the virus. Our results will help develop therapies of disease due to HHV-6.