Impact of High-Frequency HLA Haplotypes on Clinical Cytomegalovirus Reactivation in Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Some studies support the hypothesis that HLA genes and haplotypes evolved by natural selection through their protective abilities against specific infectious pathogens. However, very little is known regarding the impact of high-frequency HLA haplotypes on the risk of relevant infectious diseases among a given ethnic group. We evaluated the impact of high-frequency HLA haplotypes on cytomegalovirus (CMV) reactivation and infection in allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a Japanese population as a model of infectious disease that has coexisted with humans. A total of 21,127 donor-patient pairs were analyzed. HLA-A-B-DRB1 haplotypes were estimated using the maximum probability algorithm. Seven haplotypes with >1% frequency were defined as high-frequency haplotypes (HfHPs). Homozygotes of HfHP and heterozygotes had significantly lower risk of CMV reactivation and infection (hazard ratio [HR] = 0.88, P = .009 and HR = 0.93, P = .003, respectively) than homozygotes of low-frequency HLA haplotypes (LfHPs). In subgroup analyses of a different donor source, these associations were statistically significant in unrelated donor transplants. Finally, CMV risk for homozygotes and heterozygotes of each HfHP was compared with that of homozygotes of LfHPs. The 2 most predominant HfHP groups (A*24:02-B*52:01-DRB1*15:02 group and A*24:02-B*07:02-DRB1*01:01 group) had a significantly lower risk of CMV reactivation and infection (HR = 0.86, P < .001 and HR = 0.91, P = .033, respectively). Our findings suggest that HfHPs may be protective against CMV reactivation and infection and that increased care regarding CMV reactivation and infection may be necessary for patients with LfHP after allo-HSCT.

Significance of Cytomegalovirus gB Genotypes in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation: Insights from a Single-Centre Investigation

“…However, in immunocompromised individuals, CMV can lead to severe diseases such as encephalitis, pneumonitis, hepatitis, uveitis, retinitis, and gastrointestinal issues. Notably, CMV is a frequent cause of congenital infections and a common contributor to central nervous system complications in newborns, such as mental retardation, cerebral palsy, and seizures [ 5 ]. In the context of immunocompromised patients, CMV infection poses a significant challenge, particularly after allogeneic hematopoietic stem cell transplantation (HSCT), resulting in considerable morbidity and mortality [ 6 ].…”

Major histocompatibility complex: history of discovery, evolution, structure, significance in transplantation of allogeneic hematopoietic stem cells

“…Система HLA, играя большую роль в осуществлении механизмов противоинфекционного и противоопухолевого иммунного ответа, может определять предрасположенность к развитию некоторых аутоиммунных и вирусных заболеваний. Так, было показано, что наиболее часто встречаемые HLA-гаплотипы обладают меньшей восприимчивостью ко многим инфекционным заболеваниям, в том числе к цитомегаловирусу (ЦМВ), вследствие эволюционного преимущества [56]. Показано, что реципиенты аллогенной почки с HLA-B*44 более подвержены инфицированию ЦМВ по сравнению с пациентами без этого аллеля; напротив, реципиенты почки с HLA-DRB1*01 были более подвержены инфицированию ЦМВ, чем пациенты без этого аллеля [57]…”