Mark Gudesblatt, MD

tainment of JCV in the CNS as well as influencethe clinical outcome. 21 In a study exploringthis hypothesis, autopsy samples from 26AIDS-related and 20 non–AIDS-related casesof PML were evaluated. In the tissue samples,the predominant inflammatory cells wereCD8+ T-lymphocytes, which were closely associatedwith JCV-infected glial cells. The authorsspeculated that these cell populations could becrucial to the immunosurveillance that determinesrisk and the extent of a productive JCVinfection in the CNS, providing a potentiallyuseful target for understanding relative risksand determining targets of therapy.JCV is characterized as an opportunisticinfection because of its ability under specificcircumstances to transform from a benignresident microbe to a productive pathogen,but there may be variability in the molecularevents leading to PML in individuals withAIDS relative to individuals who develop PMLas a complication of an immunomodulatingtherapy. 22 For example, the viral load of JCVin the CNS has been identified as a predictorof survival in AIDS-related PML, but severeimmune deficiency in these patients may differfrom the alterations in immune functioncurrently suspected of mediating risk of PMLamong those taking an immunomodulatorytherapy. While antiretroviral therapies havebeen associated with a reduction in the JCVviral load in the CNS and an improvement insurvival, 23 the strategy for preventing PML orcontrolling JCV after the demyelinating diseasehas developed is likely to be different inpatients whose underlying risk has been dueto persistent exposure to an immunomodulatingtherapy.Survival and Risk StratificationPML is not necessarily a fatal disease, despitetraditional dogma. The high rates of fatalityduring the AIDS epidemic before the introductionof effective antiretroviral rates were observedirrespective of PML. In the current era,slightly more than half of AIDS patients whodevelop PML are alive at one year, and the raterises to nearly 60% in patients with PML withanother etiology, such as exposure to an immunomodulatingtherapy. 24 In patients with AIDS,an immune reconstitution inflammation syndrome(IRIS) was associated with a lower rateof survival at one year (53% vs 65%), althoughthis difference did not reach statistical significance.A low CD4+ count was also a risk factorfor PML-related mortality in AIDS patients, althoughthe presence of JCV-specific CTLs wasassociated with a trend for improved survival.Other data support the role of JCV-specificCTLs as predictors of survival in PML. In astudy employing a highly sensitive assay for detectingthe cellular immune response to JCV inpatients with PML, JCV-specific CTLs seemedto limit progression of brain lesions. 25 The authorssuggested that the same mechanism mayprevent PML altogether in many patients bymechanisms analogous to control of cytomegalovirus(CMV) and Epstein-Barr virus (EBV).One of the likely mechanisms of CTLs in regardto survival among those who develop PML isa reduction in viral production and CNS damage.In one series of 12 patients with PML thatdemonstrated a wide variation in the JCV viralload, greater JCV burden could not be associatedwith the magnitude of neurological damage,but higher viral loads did correlate with shortersurvival time. 26Several strategies are being pursued forPML risk stratification and for predicting diseasecourse in those who develop PML. In astudy that sequenced the genomic coding regionsof the VP1-associated–specific polymorphicresidues at specific positions of the outerloop, some appear to be associated with a morefavorable prognosis. 27 As the external loopsare thought to provide the principal antigenicstructures as well as receptor-binding sites anddomains responsible for hemagglutination,these regions may be valuable for identifyingJCV with a low propensity for CNS infection aswell as a more benign course of PML. Goreliket al 28 found VP1 mutations in CSF and bloodsamples isolated from PML patients, but noturine samples, suggesting that mutations occurafter infection with archetype virus.Due to a far larger sample size, more dataare available regarding predictors of survivaland potential therapies in AIDS-related PML.S14 July 2011 • Clinical Reviews of JCV and PML