Mark Gudesblatt, MD

JCV exposure than those who are not immunocompetent.42 Lower viral loads in the CSFhave been correlated with better survival inHIV-infected patients with PML, 43 but characteristicsof the JCV may be equally as importantfrom the prognostic perspective. Forexample, polymorphisms in the VP1 caspidcoding region have been associated with lessvirulent PML and slower progression. 44Ultimately, it is likely that PML has beena very rare event except in individuals withAIDS because of an array of barriers that diminishthe risk. These have been groupedinto viral barriers, host barriers, and immunologicalbarriers. 45 The key viral barrier appearsto be the need for JCV to undergo a geneticrearrangement of its promoter regionto produce a transformation that will permitinfection of oligodendrocytes. Host barriers,although not yet identified, are presumedbecause overt PML is rare compared to thefrequency of JCV infection. The immunologicalbarriers include JCV-specific cytotoxic Tcells, but other types of cell-mediated immunityare suspected to be involved. 45PML occurs in a very small proportion ofindividuals at risk. The highest rate of PML,observed in patients with AIDS, is approximately4% to 5%. In contrast, the rates of PMLwith immunomodulating therapies are typicallyless than 0.01%. 4 Although PML is a seriousdisease, it is not necessarily fatal in allcases, as evidenced by an approximate 70%survival rate in natalizumab-treated PMLcases, 5 encouraging efforts to identify characteristicsof the virus and of the host defensethat may be important for improving prognosis.While assaying JCV DNA in the blood orurine of patients prior to treatment with animmunomodulating therapy to predict riskof PML does not appear to be effective, 46 thisnot only highlights the insensitivity of currentDNA detection methods, it may also suggestthat the presence of JCV is not as importantas the interrelationship of the virus to the immunedefenses. This is a logical assumptionfrom the frequency of JCV exposure in thegeneral population and the marked infrequencyof PML even in highly immunocompromisedpatients.ConclusionEstimates vary, but many experts believe thatthe majority of the human population harborsJCV. In most individuals, the virus, after a primaryinfection in childhood, resides in tissuereservoirs, replicating at very low levels. Althoughasymptomatic reactivation may occur,there appear to be no clinical consequencesin the vast majority of cases. The exceptionsinclude productive infection of oligodendrocytesand other brain cells, leading to the demyelinatingdisease PML. Prior to the AIDSepidemic, PML was exceedingly rare, and itremains rare outside of this disease. Based ona multitude of clinical observations, severalfactors must be present for PML to occur. Thefirst two are infection with mutant, pathogenicforms of JCV and an immunocompromisedstate. However, some additional factor or factorsare likely to be essential. Even in cases ofprofound immunodeficiency, such as AIDS,only a small minority of patients developPML. When associated with immunomodulatingor immunosuppressant agents, PML iseven rarer by several orders of magnitude andtypically occurs only after extended exposure.To date, the mechanisms by which latentJCV transforms into a pathogenic infection inthe CNS remain incompletely understood butmay involve both the characteristics of theJCV as well as specific processes in immuneresponse. The infrequency of PML complicatesefforts to isolate the mechanisms thatdistinguish those immunocompromised patientswho develop PML from those who donot, but there are several promising avenuesof research. The effort to isolate the specificmolecular steps is being actively investigatedfor their potential to permit those at variouslevels of risk to be detected and stratified interms of risk-benefit ratio in advance of therapyor to be treated appropriately to abort theactive PML infectious process. Clinical Reviews of JCV and PML • July 2011 S7