Coinfection with Human Cytomegalovirus Genetic Variants in Transplant Recipients and Its Impact on Antiviral T Cell Immune Reconstitution

Corey Smith, Rebekah M. Brennan, Siok-Keen Tey, Mark J. Smyth, Scott R. Burrows, John J. Miles, Geoffrey R. Hill, Rajiv Khanna

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. Infection and disease caused by human Cytomegalovirus (CMV) remains a significant burden in patients undergoing haematopoietic stem cell transplantation (HSCT).The establishment of efficient immunological control, primarily mediated by cytotoxic T cells plays a critical role in preventing CMV-associated disease in transplant recipients. Recent evidence has also begun to investigate the impact genetic variation in CMV has upon disease outcome in transplant recipients. In this study we sought to investigate the role T cell immunity plays in recognising and controlling genetic variants of CMV. We demonstrate that while a significant proportion of HSCT recipients may be exposed to multiple genetic variants of CMV, this does not necessarily lead to immune control mediated via recognition of this genetic variation. Rather immune control is associated with the efficient establishment of a stable immune response predominantly directed against immunodominant conserved T cell epitopes.