Reconstitution of the virus-specific CD8 T-cell response is crucial for the prevention of human cytomegalovirus (CMV)-associated pathogenesis in transplant patients and human immunodeficiency virus-infected individuals. Although adoptive T-cell immunotherapy has been used successfully in various clinical settings, prophylactic vaccination remains the most amenable strategy to prevent CMV disease. However, vaccination in clinical settings where the host is severely immunocompromised due to the loss of CD4 T cells remains a significant challenge. This study investigated the efficacy of a chimeric CMV vaccine in a model setting that allowed studies on the generation of CD8 T-cell memory responses in a transient CD4 T-cell-deficient setting similar to that seen in immunocompromised patients. Immunization with an adenoviral CMV vaccine under transient helpless (complete CD4 T-cell depletion) or help-deficient (partial CD4 T-cell depletion) conditions demonstrated that induction of the effector CD8 T-cell and humoral responses was almost completely eliminated under helpless conditions, and was gradually regained with the recovery of CD4 T cells. However, this response failed to protect the host from viral infection, suggesting that lack of CD4 T cells during vaccination can significantly impair the priming and maturation of CMV-specific immune responses. Furthermore, although the induction of CMV-specific immune responses was also significantly reduced in a help-deficient environment, these primed effector cells could mature normally and generate long-term polyfunctional memory responses capable of restricting virus replication . These results highlight the importance of monitoring CD4 T-cell numbers before vaccination for the successful implementation of a CMV vaccine in an immunocompromised setting.


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