History and current concepts in the pathogenesis of PML
ABSTRACTThe JC virus (JCV), first described in 1971, is responsible for initiation of progressive multifocal leukoencephalopathy (PML), a disease characterized by demyelinating plaques and a classic triad of symptoms consisting of cognitive impairment, visual deficits, and motor dysfunction. To establish a diagnosis of PML, evidence of the presence of JCV DNA in pathologic tissue is necessary. The host range for productive infection of JCV is controlled by factors in the cell nucleus that bind to the viral promoter, initiating transcription of mRNA for the coordinated synthesis of viral proteins. Oligodendrocytes, astrocytes, and CD34+ and CD19+ cells of the immune system have the necessary binding proteins in sufficient concentration to allow lytic infection to occur. A strong link between JCV infection in cells of the immune system and cells of the nervous system points to the importance of the tissue origin of JCV latency, the bone marrow that harbors CD34+ cells. The emergence of PML in patients treated with natalizumab and other immune-altering agents supports this observation and provides new insights into the pathogenic mechanisms of JCV infection.
SUMMARY
Despite the prevalence of JCV in the population, the development of PML is rare. Levels of JCV antibody rise during the course of active JCV infection, but they do not protect against infection. T-cell responses directed to structural and nonstructural proteins play a role in controlling infection. Latency of JCV is associated with specific cells of the immune system, and its reactivation can follow alteration of normal immune cell function—either immunosuppression or immunomodulation. Risk factors for the development of PML include rising antibody titers and ineffective T-cell (CD4 and CD8) responses.
DISCUSSION
Dr. Berger: Does natalizumab upregulate Spi-B in glial cells?
Dr. Major: We never tested this directly. From human brain cultures, we know that Spi-B is made in glial cells, not in neurons. We are considering the idea that wherever JCV binds, it takes advantage of certain types of DNA-binding proteins in the molecular regulation. If the binding takes place in an immune system cell, for example, Spi-B plays an important role.
Dr. Berger: Koralnik et al demonstrated JCV excretion in urine in MS patients after 12 months of treatment with natalizumab, and at 18 months, viremia in 60% of the patients.20 Yet, repeated studies of patients taking natalizumab have failed to demonstrate viremia or conversion of virus in the archetype. How do these findings correlate with your thoughts on the action of natalizumab in the pathogenesis of PML?
Dr. Major: We certainly know that natalizumab forces migration of hematopoietic stem cells and pre-B cells out of the marrow, but our findings have differed somewhat from those of Koralnik’s laboratory. For example, in the several hundred nucleotide sequences we have looked at in PML brain tissue, we have found the Mad 1 genotype once. We consider Mad 1 to be a potential laboratory contamination, so if we find Mad 1 we resequence the sample. We never clone because cloning can introduce alterations; we sequence directly from the clinical tissue. We can identify Mad 1 because our assay is very sensitive. In normal individuals, CD34+ cells compose approximately 0.01% of the peripheral circulation; in individuals treated with natalizumab, however, their composition is 0.1% to 0.3%. So if there is a potential for latent infection, we have an opportunity to find it in those cells. Its presence does not necessarily mean that the individual is going to develop PML, however; there are other controlling factors.
Dr. Rudick: Have you found the virus in B cells in healthy people?
Dr. Major: Yes we have, in about one-third. It is higher than what we would expect to see in the normal population.
Dr. Rudick: How can that finding be turned into something that’s clinically useful?
Dr. Major: If you’re trying to identify persons who are more susceptible to PML given underlying risk factors—treatment with natalizumab or rituximab, presence of HIV infection, or some other immune-altering condition—looking at one parameter isn’t going to help. Based on the available data, rising antibody titers signals an active infection, and viremia of any kind means probable latent infection. Because this is a small event in very few cells, you will not have the numbers of cells needed to identify susceptibility in a normal population. For now, we monitor patients at risk and, if we find viremia, we assess the cell population to determine whether a molecular factor like Spi-B is upregulated. We hope to develop an assay in which we can obtain one test tube of blood and report T-cell responses, molecular factors, antibody titer, and presence or absence of viremia. Such an assay would provide the data necessary to make a clinical decision.
