Coinfection with human cytomegalovirus genetic variants in transplant recipients and its impact on antiviral T cell immune reconstitution

Reconstitution of T cell immunity is absolutely critical for the effective control of virus-associated infectious complications in hematopoietic stem cell transplant (HSCT) recipients. Co-infection with genetic variants of human cytomegalovirus (CMV) in transplant recipients has been linked to clinical disease manifestation, however how these genetic variants impact on T cell immune reconstitution remains poorly understood. Here we have evaluated dynamic changes in the emergence of genetic variants of CMV in HSCT recipients and correlated these changes with reconstitution of anti-viral T cell responses. Analysis of single nucleotide polymorphisms within sequences encoding HLA class I-restricted CMV epitopes from the immediate early 1 gene of CMV revealed that co-infection with genetically distinct variants of CMV was detected in 52% of patients. However in spite of exposure to multiple viral variants, the T cell responses in these patients were preferentially directed to a limited repertoire of HLA class I-restricted CMV epitopes, either conserved, variant or cross-reactive. More importantly, we also demonstrate that long-term control of CMV infection after HSCT is primarily mediated through the efficient induction of a stable anti-viral T cell immunity irrespective of the nature of the antigenic target. These observations provide important insights for the future design of anti-viral T cell-based immunotherapeutic strategies for transplant recipients emphasising the critical impact of robust immune reconstitution for efficient control of viral infection