Mark Gudesblatt, MD

tive therapies appear to exert some change onthe relationship between the virus and the CNSbut impose little or no direct effect on the replicationrate of the pathogen. Although one smallstudy did associate natalizumab with reactivationof JCV, a much larger study was unable todemonstrate any change in JCV-DNA positiveurine specimens after 48 weeks of natalizumabtreatment. 6 In a series of five patients who diddevelop PML, there was no change in JCV DNAlevels prior to disease onset.There are at least 14 currently availablegenotypes, which are determined by the codingregion of JCV. 8 While genotypes have notbeen well matched with virulence, changes inthe hypervariable regulatory region do appearto control the transformation from an archetypelatent JCV to an opportunistic neurotropicinfection with propensity for PML. 5 However,the transformation from the archetype formof the virus to the PML-capable infection doesnot appear to be fully explained by alterationsin the biology of the virus. 16 Rather, in aseries of experiments conducted in the presenceof the JC virus T antigen, the replicationand transcription functions were remarkablysimilar between the archetype and virulentstrains, producing the hypothesis that archetypestrains do not have to convert to PML-typestrains to infect cells in the CNS. This suggeststhat the conversion to the virulent form may, inat least some cases, take place after JCV infectscells in the CNS.The site of the latent JCV infection may alsobe relevant to risk of PML. Low levels of replicationin the bone marrow or lymph tissue, forexample, may pose a much greater risk that thevirus will reach the CNS than latent infection inrenal tissue, particularly when immunomodulatingtherapies alter lymphocyte function. Inone study, JCV virus could be detected in thebone marrow of about twice as many patientswith PML, whether associated with AIDS oranother etiology, than those without PML. 17Although the ability of JCV to reside in the CNSin a latent state is controversial, the potentialfor CNS latency to serve as a risk factor for PMLdeserves further evaluation. If CNS latency isan uncommon but necessary event, this mayexplain the infrequency with which PML isa treatment-related complication. However,autopsy studies suggest that JCV is capable ofcrossing the BBB without producing a demyelinatingdisease, 18 which, again, supports thelikelihood that the presence of JCV in the CNSalone is not a sufficient reason by itself for PMLto occur.One theory is that cell susceptibility to JCVinternalization is required independent of thepresence of receptors known to be used bythis virus for attachment. The nuclear factor-1(NF-1) class X protein, for example, has beenfound at higher levels in JCV-susceptible cellsthan nonpermissive cells, leading to speculationthat expression of this receptor, or additionalreceptors, such as c-Jun, are necessaryfor virus to infect cells critical to PML disease. 19While it has been proposed that activation ofB-lymphocytes by immunomodulating therapies,such as rituximab or natalizumab, play acritical role in transporting JCV across the BBB,this, again, may be one of several molecularevents that must occur for PML to develop.The many unresolved issues complicatethe effort to isolate the steps that permit benign,archetypal JCV to mount a productiveand virulent infection of the CNS. Followinga report of rituximab-related PML, monitoringof blood for JCV and BK virus, anotherpolyomavirus, was performed in 73 consecutivepatients who received rituximab as partof a therapeutic regimen following solid organtransplantation. 20 Over a median 13 months offollow-up, JCV was detected with polymerasechain reaction (PCR) in the blood of four patients(5.5%). Loss of cell-mediated immunityappeared to correspond with JCV detection,but JCV could not be detected in the blood ofany of the four individuals with subsequentmonitoring. None developed PML or any clinicalevidence of neurologic disease. In contrast,all 73 patients developed BK-associated nephropathy,prompting a reduction in the immunosuppressionregimen.In patients who already have PML, an evaluationof the cell-mediated immune responsesuggests that CD8+ cytotoxic T-lymphocytes(CTLs) may play a critical role in the early con-Clinical Reviews of JCV and PML • July 2011 S13