Progressive multifocal leukoencephalopathy (PML) is a severe infection of the central nervous system occurring in immunocompromised individuals in which large demyelinating lesions are induced by polyomavirus JC (JCV). In the absence of effective antiviral treatment, control of the infection relies on restoring anti-JCV immunity. Thus, particularly in longstanding immunocompromising conditions such as organ transplantation, lymphoproliferative disorders, or idiopathic lymphopenia, new strategies to boost anti-JCV immune responses are needed. Here, we report the case of a patient developing PML in the context of kidney transplantation who received rh-IL-7 to foster immune responses against JCV. We give an overview of the immunological mechanisms underlying the development of PML and immune restoration within the central nervous system following JCV infection. Immunotherapeutic strategies developed based on current understanding of the disease hold promise in managing patients with PML.