In situ evidence of JC virus control by CD8+ T cells in PML-IRIS during HIV infection

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Abstract
Objective: To determine the pathophysiologic features of progressive multifocal leukoencephalopathy (PML) associated with immune reconstitution inflammatory syndrome (PML-IRIS) in HIV-infected patients. Methods: In a cross-sectional study, we retrospectively analyzed 11 HIV-infected patients with a firm diagnosis of PML-IRIS. Brain biopsies were collected from 5 patients and their histopathologic features were compared to those of 4 HIV-infected patients with classic PML. Results: PML-IRIS developed soon after initiation of antiretroviral therapy in late-presenting HIV-infected patients. The lesions from the 5 biopsied PML-IRIS patients were characterized by a reduction in the density of JC virus (JCV)–infected cells when compared to the 4 patients with PML (11.1 ± 3.2/mm2 vs 51.2 ± 4.3/mm2, p = 0.01). Comparing the 5 patients with PML-IRIS vs the 4 patients with PML, this correlated with an increased accumulation of CD8+ T cells (818.2 ± 192.8/mm2 vs 52.5 ± 10.6/mm2, p = 0.01), CD20+ B cells (33.4 ± 13.5/mm2 vs 0.5 ± 0.5/mm2, p = 0.01), and CD138+ plasma cells (177 ± 84.1/mm2 vs 0.25 ± 0.25/mm2, p = 0.01), while the number of CD68+ macrophages/microglia did not differ. The ratio between CD8+ T cells and JCV-infected cells was 70 times higher in the 5 patients with PML-IRIS. These findings indicate a clear relationship between an enhanced recruitment of CD8+ T cells and the associated control of the JCV infection. Conclusions: Our data provide in situ evidence that PML-IRIS brain lesions are enriched in cytotoxic CD8+ T cells that engage JCV-infected oligodendrocytes. This leads to a better control of JCV dissemination, but at the cost of oligodendrocyte cell death and demyelination.