JC polyomavirus (JCV) and monoclonal antibodies: friends or potential foes?

Abstract

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS), observed in immunodeficient patients and caused by JC virus ((JCV), also called JC polyomavirus (JCPyV)). After the HIV pandemic and the introduction of immunomodulatory therapy, the PML incidence significantly increased. The correlation between the use of natalizumab, a drug used in multiple sclerosis (MS), and the PML development of particular relevance. The high incidence of PML in natalizumab-treated patients has highlighted the importance of two factors: the need of PML risk stratification among natalizumab-treated patients and the need of effective therapeutic options. In this review, we discuss these two needs under the light of the major viral models of PML etiopathogenesis.

Figure 1

Development of progressive multifocal leukoencephalopathy during natalizumab treatment. This figure summarizes the three hypotheses on how natalizumab may lead to PML. (a) Natalizumab may prevent the entry of JCV-specific cytotoxic T cells into the brain, necessary for the control of latent JCV within infected oligodendrocytes. (b) Natalizumab inhibits the VLA-4-dependent homing and retentions of lymphocytes in bone marrow (sites of JCV latency), thus leading to an increase of JCV-infected peripheral leukocytes. Finally, another possible factor is the natalizumab-induced expression of Spi-B, a transcription factor that has been shown to increase JCV transcription.

Figure 2

Immunofluorescence staining of COS7 infected by JCV (Mad4), five day after infection. The cells were stained with anti-VP1 monoclonal antibody (green-stained cells) and counterstained with Evans blue (red-stained cells).

Figure 3

Mechanisms of PML pathogenesis. The necessary condition for the PML developments is that oligodendrocytes are infected by JCV. In this figure the three ways through which the virus could cross the BBB are represented: (a) as free virus or (b) the infection of the endothelial cells of the barrier by JCV-infected B cells (c) using the B cells as “a Trojan horse.”