Progressive multifocal leukoencephalopathy: clinical and molecular aspects

Abstract

The fatal CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML), is rare and appears to occur almost always as a consequence of immune dysfunction. Thus, it is associated with HIV/AIDS and also as a side effect of certain immunomodulatory monoclonal antibody therapies. In contrast to the rarity of PML, the etiological agent of the disease, the polyomavirus JC (JCV), is widespread in populations worldwide. In the 40 years since JCV was first isolated, much has been learned about the virus and the disease from laboratory and clinical observations. However, there are many aspects of the viral life cycle and of the pathogenesis of the disease that remain unclear, and our understanding is constantly evolving. In this review, we will discuss our current understanding of the clinical features of PML and molecular characteristics of JCV and of how they relate to each other. Clinical observations can inform molecular studies of the virus, and likewise, molecular findings concerning the life cycle of the virus can guide the development of novel therapeutic strategies.

Figure 1. MRI of a case of PML

Shown is an axial T2 weighted sequence showing multiple hyperintese lesions involving both the superficial and the deep white and the grey matter (arrows).

Figure 2. Life cycle of JCV and therapeutic targets

The steps in the life cycle of JCV are indicated by numbers in black as follow: 1 - adsorption of virus to cell surface receptors; 2 -entry by clathrin-dependent endocytosis; 3 - transport to the nucleus; 4 - uncoating; 5 -transcription of the early coding region; 6 - translation of early mRNAs to produce the early regulatory proteins, large T-antigen, small t-antigen and the alternatively spliced T′-antigens: T′135, T′136 and T′165; 7 - Nuclear localization of large T-antigen; 8 - replication of viral genomes; 9 - transcription of the viral late genes; 10 - translation of viral late transcript to produce agnoprotein and the capsid proteins (VP1, VP2 and VP3); 11 - nuclear localization of capsids; 12 - assembly of viral progeny in the nucleus; 13 - release of virions by an unknown mechanism; 14 - released virions. Targets for drug intervention are indicated by letters in red as follows: A - virus/receptor interaction; B - viral entry; C - viral replication; D - viral transcription.