Mark Gudesblatt, MD

VP1 capsid protein are associated with the developmentof PML. 33 Ultimately, understandingthe transformation of JCV to its virulentforms may be a more important target of controlthan promoting immune response.The factors that alter the NCCR of JCV toincrease its pathogenicity have been difficultto isolate in the absence of an animal model.Several proteins implicated in cell-type–specificregulation of JCV DNA transcriptionhave been isolated. For example, substantialresearch has been devoted to evaluatingwhether NF-1X, which is a member of theNF-1 family of functional proteins, is involvedin modification of JCV gene function. In humanglial cell lines, expression of NF-1X hasbeen associated with increased susceptibilityto JCV. 34 Conversely, loss of susceptibilityto JCV infection has been associated withloss of NF-1X expression. Other DNA-bindingproteins, such as c-Jun and GBP-1, have alsobeen pursued for their ability to alter nucleotidesequence arrangements in the JCV regulatoryregion.Due to the variability in outcomes ofPML, the relative pathogenicity conferred bychanges in the regulatory genes of JCV is likelyto be an important factor. These rearrangementsmight act on numerous variables thatinfluence the ability of JCV to produce PMLor affect its severity. One classification systemattempted to match sequence differencesin JCV variants with characteristic behavior,such as relative cell tropism in the CNS andrates of replication. 35 The interaction betweenthe genetic transformation of JCV from its archetypeand its relative ability to predict riskof PML or even risk of adverse outcomes inthose who develop PML may lead to insightsabout mechanisms of pathogenesis and opportunitiesto intervene.One of the most important questions inthe effort to understand the relationship ofJCV and PML is whether the transcriptionchanges needed to confer pathogenicity to thevirus occur in virus replicating at low rates inthe kidney or bone marrow or in virus alreadypresent in the CNS. While JCV was originallyconsidered neurotropic because it was firstisolated in the brain, it was then thought to berare or absent in the CNS except during activedisease. The evidence that JCV can be foundin the CNS in the absence of PML raises thepossibility that the transcription changes occurin the brain under some impetus related tochange in immune function rather than a viralreactivation outside of the CNS that producesPML when it crosses the BBB. 36 The effort todevelop consistent theories is challenged bysome apparently contradictory findings, suchas the identification of the same viral strainin the urine of patients without PML and thebrain of patients with PML. 37 Mutations inthe archetypal virus in patients with PML areidentified in the CSF and blood, suggestingthat mutation occurs after primary infectionwith the archetypal virus.One of the most likely transporters of JCVacross the BBB, whether the virus is in a quiescentor activated state, is B-lymphocytes.JCV-infected B-cells have been detected inthe brains of patients with PML, 38 but transmigrationacross the BBB may not alone besufficient for PML to occur, particularly if JCVhas not undergone the changes that wouldallow it to express proteins needed for cellbinding. It is possible that transmigration ofJCV into the BBB is not directly related to therisk of PML. Rather, this transmigration mayoccur in both individuals who do and whodo not develop a demyelinating disorder, indicatingthat some further step is needed forproductive infection of oligodendrocytes.A complex relationship between immunedefenses and JCV is further suggested by theinconsistent relationship between the presenceof JCV-specific antibodies and protectionagainst PML. Although the level of antibodieshas not been found to correlate withprotection against PML, 39 there is preliminaryevidence that JCV-specific cytotoxic T-lymphocytes(CTLs) prevent or slow PML progression.40 CD8+ lymphocytes are also beingevaluated for their ability to defend againstPML. While high numbers of CD8+ cells havebeen observed near active PML lesions, 41 immunocompetentindividuals have been foundmore likely to have a CD8+ T-cell response toS6 July 2011 • Clinical Reviews of JCV and PML