Viral evolution with selection of strains that can infect the brain leads to PML. #ResearchSpeak #MSBlog #MSResearch
“It looks as if readers of this blog have more than a passing interest in how JCV (John Cunningham Virus) causes PML. So here is part 1 of a complicated story; apologies if you don’t understand it, it requires some background knowledge about viral evolution.”
“As with a lot of delayed viral infections of the brain JCV requires the wild-type virus to mutate and acquire the ability to infect the brain. Interestingly, this concept is not new and JCV joins a well-known list of neurotropic viruses (viruses that can infect the central nervous system) that do this. This list include the relatively well known measles, rubella and herpes simplex viruses. All these viruses have mutant strains that can infect the brain.”
“In this JCV genomic study below you can see that the vast majority of JCV strains from the spinal fluid of patients with PML have acquired several mutations in their viral capsid protein (VP1) that are associated with altered binding to well defined cellular targets on the surface of cells. In short these mutant strains of JCV lose their ability to bind to peripheral cells and acquire the ability to bind to brain cells. Interestingly, these mutant JCV strains are also found in the blood, but not the urine. I therefore suspect they spill out from the brain, and spinal fluid, into the blood where they can be detected. However, the mutant JCV strains are not found in the urine as the urine JCV strains come from viral replication in the kidney. Why do I say this? JCV does not have a latent phase and to maintain itself it needs to cause a continuous infection cycle; this cycle causes lytic infection and with each cycle of replication it destroys the cell it infects, i.e. lyses or kills it. If the mutant strains lose the ability to infect peripheral cells and acquire the ability to infect brain derived cells, the ongoing infection is therefore likely to be in the nervous system; i.e. a pre-PML state. In normal people immune surveillance will keep these pre-PML mutant strains at bay, which is why PML in people with normal immune systems is so rare. However, if you interrupt immune function a small number of people will get PML; these people may be predisposed to PML by having wildtype virus already in the brain. At present we don’t know how wildtype virus gets to the brain; some researchers think JCV piggy-backs a ride on immune cells that traffic to the brain, in particular B cells. The story is very different with agents, such as natalizumab, that block trafficking of immune cells to the brain. This essentially gives the JCV, that may already be in the brain, the freedom to mutate at will without any interruptions from immune surveillance. This form of viral evolution allows nature to select a mutant strain of JCV that eventually causes PML. This is why the incidence of PML in natalizumab-treated MSers is orders of magnitude higher than that with other immunosuppressive agents. At least other immunosuppressive agents allow some immune surveillance to occur albeit slightly suppressed. I hope all this makes sense.”
“The obvious question is that if you have pre-PML strains of JCV already and you stop natalizumab do you think the immune system will find all the mutant viruses and kill them? Or do you think a few viruses will escape immune surveillance and maintain themselves to cause PML later? I favour the latter scenario particularly if you are switched from natalizumab to a DMT that is immunosuppressive; any DMT that affects immune function will simply increase the chances of pre-PML strains surviving and eventually mutating into a PML causing strain. This is why I don’t accept Biogen’s stance that the latest, and fourth, case of PML on dimethyl fumarate (DMF, Tecfidera) has nothing to do with natalizumab. Do you really accept viral evolution unwinding itself?”
“These observations and theoretical constructs have implications for switching strategies in that you don’t really want to switch MSers who are at high risk of PML to immunosuppressive agents post-natalizumab. This is why daclizumab and ocrelizumab will be such valuable DMTs options post-natalizumab. Daclizumab is an immunomodulator that does not appear to have a major effect on effector T-cell function and induces a population of NK cells that are part of the innate immune system that fight viral infections. Similarly, ocrelizumab depletes B-cells, but leaves T-cell effector function intact, which should be able to deal with both pre-PML and PML strains of mutant JCV. We know from the HIV-AIDS era that T-cell effector function is more important than B-cells in curing people of PML. Other DMTs that are not immunosuppressive include interferon-beta and glatiramer acetate, but these agents are not as efficacious as daclizumab and ocrelizumab and are therefore unlikely to used much in this situation. In addition, most MSers on natalizumab have previously had a suboptimal response to these agents hence the need for them to be on natalizumab to control their MS disease activity.”
“It is clear that the management and treatment of MS is becoming increasingly complex, which is why MS is best managed by teams of MS experts.”
Gorelik et al. Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis. 2011 Jul 1;204(1):103-14.
Background: Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes, may develop in patients with immune disorders following reactivation of chronic benign infection. Mutations of JCV capsid viral protein 1 (VP1), the capsid protein involved in binding to sialic acid cell receptors, might favor PML onset.
Methods & Results: Cerebrospinal fluid sequences from 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in paired plasma but not urine sequences despite the same viral genetic background. VP1-derived virus-like particles (VLPs) carrying these mutations lost hemagglutination ability, showed different ganglioside specificity, and abolished binding to different peripheral cell types compared with wild-type VLPs. However, mutants still bound brain-derived cells, and binding was not affected by sialic acid removal by neuraminidase.
Conclusions: JCV VP1 substitutions are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid binding with peripheral cells, while maintaining sialic acid-independent binding with brain cells.