Mark Gudesblatt, MD

us of the genus Papovaviridae that was firstisolated at about the same time, JCV is presentin the majority of the human population.7 Infectivity rates are highly varied (33%to 91%) 8 depending on the method of detectionused and the age, gender, and underlyingstatus of the population being tested. JCVis currently felt by some to be typically acquiredin childhood, adolescence, or youngadulthood. 9 Although some believe that themajority of infections are acquired before age10, the risk for exposure and infection continuesthroughout adulthood. 10 The primaryinfection appears to occur in tonsil or gastrointestinalepithelial cells. 11 At the time of acquisitionand throughout its latent state, theinfection remains asymptomatic. 1After primary infection, latent JCV canpersist lifelong in one or more of several tissues,most likely the kidney, the bone marrow,and the lymph glands. 12 Latent infection in theCNS is possible, but its frequency and relativeimportance to PML are unclear. 12 AlthoughJCV infects a narrower range of cell types thanthe BK virus, other polyomaviruses, such asthe more recently identified WU and KI types,which predominately affect respiratory tissue,also appear to initially infect a relatively smallnumber of cell targets. 10One method currently identified for JCVto bind to cells is via the N-linked glycoproteinwith an alpha-(2-6)-linked sialic acid orthe serotonin 5-HT2a receptor. 13,14 It enters thecell through endocytosis. 15 At least 14 genotypesof JCV have been identified. 16 All areunique to the human host. These are associatedwith specific racial groups or geographicregions. For example, types 1 and 4 predominatein Europe, while types 3 and 6 predominatein Africa. 17The non-coding control region (NCCR)defines JCV genotypes. This region, which determinesgene regulation and viral replication,is relatively stable and may not be a strong determinantof pathogenicity. In contrast, thegene sequence of the regulatory region, whichmay be important for hematogenous spreadof the virus into the CNS, 18 has been characterizedas hypervariable. 1 Relative to the regulatoryregion of quiescent, archetypal JCV, theregulatory region of pathogenic forms of JCVin patients with PML typically contains multipledeletions and duplications. 19 Activationof the virus is associated with transcription ofthe agnoprotein as well as the VP1, VP2, andVP3 caspids, which are thought to be essentialfor viral propagation. 20 Other proteins transcribedin the regulatory region of the genomemay interfere with T antigen functions. 21 Forthese reasons, reconfiguration of the NCCR isconsidered to be important to both the neurotropismand the neurovirulence that is likelyto define the risk of PML.JCV infection, presumed to have coexistedin the human population for millennia, is sufficientlyubiquitous that it has been proposedas a target of the co-divergence studies employedto trace both human migration andevolution. 22 Although subsequent analysesdetermined that the phylogeneses of JCV andhumans are not sufficiently similar to servethis purpose, 16 the polyomaviruses overalland JCV in particular may be useful for betterunderstanding the interrelationship betweenviral infections and human defenses. Recognizedfor only 50 years, the five human polyomaviruses,which, in addition to the JC, BK,WI, and KU viruses, include the Merkel virus,are all seen with high prevalence rates butwith low risk of clinical disease. 10 While latentpolyomavirus infection is typical, JCV may reactivateperiodically in infected tissues, basedon viral shedding in the urine, without clinicalconsequences. 23PML: Description of Clinical FeaturesPML is the only demyelinating disorder directlylinked to an active virus. 24 The disorderis characterized by productive JCV infectionof cells in the CNS, particularly oligodendrocytes.The importance of other cell types inPML, such as astrocytes, also appears to be significant.A definitive diagnosis of PML, whichhas nonspecific clinical signs and symptoms,is considered to be detection of JCV DNA indemyelinated lesions on brain tissue or centralspinal fluid, often with DNA hybridizationor polymerase chain reaction (PCR) amplifi-S4 July 2011 • Clinical Reviews of JCV and PML