Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS 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 long-standing 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 recombinant human interleukin 7 to foster immune responses against JCV. We give an overview of the immunologic mechanisms underlying the development of PML and immune restoration within the CNS after JCV infection. Immunotherapeutic strategies developed based on current understanding of the disease hold promise in managing patients with PML.