Influência do repertório de HLAs no desfecho da infecção por HCMV em indivíduos transplantados

Abstract

Human cytomegalovirus (HCMV) is a common human herpesvirus in most cases asymptomatic in the immunocompetent population. In cases of immunosuppression such as in transplantation, HCMV infection can reactivate and affect the outcome of the transplantation, causing changes in the clinical status of patients. Despite being recurrent, it is unknown why some transplanted patients with HCMV reactivation develop the infection severely than other patients even using the same protocols and treatments. To better understand the immune response of individuals with different outcomes in the infection, we selected transplanted patients with HCMV reactivation classified as mild infection (asymptomatic infection and less than 25 days of hospitalization) or severe (symptomatic infection and more than 25 days of hospitalization). Blood samples collected for flow cytometry analysis were stimulated with a specific peptide library for CD8 T lymphocytes (LTCD8) containing epitopes designed in silico with immunodominant regions of the five most immunogenic HCMV proteins. The results of the flow cytometry analysis demonstrated that patients who had severe infection by HCMV presented higher TNF production and increased expression of CD57 by CD8 lymphocytes (LTCD8) when compared to the group with mild infection. Furthermore, during the course of the study we observed that the HLAs used in the construction of the peptide library could be studied as a severity prediction tool. We created a score based on the number of high and intermediate affinity that each HLA molecule performs with CD8 T lymphocytes (LTCD8) epitopes of the 10 most immunogenic proteins of the virus. A score was created for each class I HLA and a value generated for each patient's HLA-I repertoire. To assess whether the HLA score of transplanted patients may be related to clinical outcome, a retrospective case-control study was performed and the medical records of patients (n=71) who had mild or severe HCMV infection were analyzed. We observed that patients with severe HCMV infection (n=31) had lower HLA repertoire scores than patients with mild HCMV infection (n=40). We also observed that the score of the HLA repertoire of patients with HCMV negatively correlate with the production of IL-10 and IL-17A by specific T lymphocytes. Studying the repertoire of HLAs and their ability to present antigens predicted in silico may have prognostic value for severe HCMV infections after transplantation.