Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation

Abstract

Key Points• We have characterized, for the first time, the cellular immune response to HHV6 and defined a hierarchy of immunodominance.• We have developed a GMPcompliant approach to generate polyfunctional T-cell lines that effectively kill HHV6-infected cells and are suitable for clinical use.Human herpesvirus (HHV) 6 causes substantial morbidity and mortality in the immunocompromised host and has no approved therapy. Adoptive transfer of virus specific T cells has proven safe and apparently effective as prophylaxis and treatment of other virus infections in immunocompromised patients; however, extension to subjects with HHV6 has been hindered by the paucity of information on targets of cellular immunity. We now characterize the cellular immune response from 20 donors against 5 major HHV6B antigens predicted to be immunogenic and define a hierarchy of immunodominance of antigens based on the frequency of responding donors and the magnitude of the T-cell response. We identified specific epitopes within these antigens and expanded the HHV6 reactive T cells using a GMP-compliant protocol. The expanded population comprised both CD4 ؉ and CD8 ؉ T cells that were able to produce multiple effector cytokines and kill both peptide-loaded and HHV6B wild-type virus-infected target cells. Thus, we conclude that adoptive T-cell immunotherapy for HHV6 is a practical objective and that the peptide and epitope tools we describe will allow such cells to be prepared, administered, and monitored in human subjects. (Blood. 2013;121(1):207-218) IntroductionAdoptive T-cell immunotherapy can successfully prevent and treat otherwise fatal infections in the immunocompromised host. At present, these benefits have been restricted to adenovirus, CMV and EBV. [1][2][3][4][5][6][7][8][9] However, it is increasingly apparent that a distinct herpesvirus, human herpesvirus 6 (HHV6) is also a significant cause of morbidity and mortality, particularly after hematopoietic stem cell transplantation (HSCT). To date, there have been no controlled studies on the use of antivirals as treatment for HHV6, but foscarnet, ganciclovir, and cidofovir have been used clinically, with variable results. [10][11][12][13][14] HHV6 is a member of the ␤-herpesvirus subfamily and exists as 2 species, HHV6A and HHV6B, which share 75%-95% nucleotide sequence identity. 15 Primary infection occurs in Ͼ 90% of individuals before the age of 2 years and is associated with clinical symptoms, including acute febrile illness and roseola infantum or exanthem subitum. 16 The virus subsequently persists in latent form, in an analogous way to other herpesviruses. Although latency is usually asymptomatic, HHV6 reactivates in Ͼ 50% of allogeneic HSCT recipients and can produce clinically significant manifestations, including encephalitis, delayed engraftment, and an increased rate of graft-versus-host disease, substantially increasing mortality. 10,11,14,[17][18][19] Thus, while HHV6 might be a suitable candidate virus to benefit from adoptive immunotherapy, such treatments can onl...

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

“…Recent studies have suggested that some peptides from HHV-6 will allow HHV-6-specific CD4 ϩ or CD8 ϩ T cells to recognize HHV-6-infected target cells, thus overcoming the immunosuppressive properties of the virus (51,52). Another challenging issue is the identification of pathogen-derived antigens which can specifically induce and activate virus-specific Treg cells.…”

Inhibition of Breast Cancer Cell Proliferation through Disturbance of the Calcineurin/NFAT Pathway by Human Herpesvirus 6B U54 Tegument Protein

“…Cancer immunotherapy protocols have demonstrated some effectiveness against virally induced disorders (27), such as in EBVinduced posttransplant lymphoproliferative disorders (28,29), but the treatment of solid tumors such as breast cancer remains a major challenge. Immunodominant epitopes derived from the HHV-6B U54 protein have been described recently (30,31). Coupled to our observation that U54 can inhibit cancer cell growth, expression of U54 in breast cancer cells could give a double advantage: first, by limiting cancer cell proliferation, and second, by "marking" the cells for anti-U54 CD8 T cell recognition and destruction.…”

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

“…Cellular immunity is believed to play the major role in this control, as reflected by the deleterious effects of T cell immune response suppression. Recent publications reported the proliferation of CD4 ϩ and CD8 ϩ T cells in response to HHV-6A and HHV-6B antigens in most healthy adults (100)(101)(102). Those studies permitted the fine characterization of a significant number of HHV-6 T cell epitopes but showed the following two important limitations for future investigations: the low frequency of circulating HHV-6-specific T cells, requiring in vitro expansion prior to any functional characterization; and the high degree of cross-reactivity between HHV-6A and HHV-6B epitopes.…”