In situ evidence of JC virus control by CD8+ T cells in PML-IRIS during HIV infection.
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.
From the Departments of Infectious and Tropical Diseases (G.M.-B., A.D., P.M., B.M.), Neuroradiology (V.C.), and Pathology (E.U.-C., M.-B.D.), Toulouse University Hospital; INSERM U1043-CNRS UMR 5282 (G.M.-B., L.T.M., R.S.L.), Centre de Physiopathologie Toulouse-Purpan; Université Toulouse III (G.M.-B., V.C., E.U.-C., P.M., M.-B.D., B.M., L.T.M., R.S.L.), France; Center for Brain Research (J.B., H.L.), Medical University of Vienna, Austria; INSERM (E.U.-C., M.-B.D.), CRCT U1087, Toulouse; and CNRS, LCC (B.M.), Université de Toulouse, France.
Guillaume
G
Martin-Blondel
Jan
J
Bauer
Victor
V
Cuvinciuc
Emmanuelle
E
Uro-Coste
Alexa
A
Debard
Patrice
P
Massip
Marie-Bernadette
MB
Delisle
Hans
H
Lassmann
Bruno
B
Marchou
Lennart T
LT
Mars
Roland S
RS
Liblau
D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology* / Q000821:virology*; D003430:Cross-Sectional Studies; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000209:etiology* / Q000473:pathology*; D007577:JC Virus / Q000378:metabolism*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013539:Simian virus 40 / Q000378:metabolism
D053804:Granzymes