Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

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Abstract
PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s). JC virus is a highly prevalent human polyomavirus. Infection with this virus is generally benign and asymptomatic despite viral persistence in the kidney of many people. However, in immunocompromised individuals, very rarely, the infection can progress to become a potentially deadly brain disease called Progressive Multifocal Leukoencephalopathy (PML). The discrepancy between very high viral prevalence and low incidence of PML suggests that there could be some unique viral characteristics that regulate the progression from the asymptomatic infection to the PML. Identification of such factors will help us to understand the basis of PML development and hopefully will lead to the creation of new diagnostic and treatment tools for managing PML. In this work, we demonstrate that the part of the viral surface protein that is thought to be responsible for viral interaction with cellular receptors and infection acquires specific mutations that appear to be critical for the development of PML. These mutations are found more frequently than by simple chance and therefore are thought to be “positively selected.” Based on these results, we hypothesize that the specific mutations in the viral VP1 protein that we have identified are critical for the evolution of JC virus to the version associated with PML.

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