Worldwide JC virus seroprevalence is 70% - 90% [1]. It is found in nature and 14 subtypes which can be isolated by specific geographic areas [2]. The virus infects children asymptomatically [3]; it remains on renal tissue and can be eliminated in urine in 40% - 75% of individuals around the age of 30 [4,5]. Its coexistence with humans without much variation through centuries has made it a useful tool for geographic migration studies [6].

This virus, without much variation, was isolated for the first time in 1971 on the brain of a Hodgkin lymphoma patient [7]. It is found associated to multiple diseases like medulloblastoma [8,9], multiform glioblastoma [10] and, Progressive Multifocal Leucoencephalopathy, an entity whose prevalence has increased during recent years and was first described by Åstrom in 1958 [11]. The JC virus or John Cunningham virus (JCV) is a polyomavirus with a circular double chain DNA 5 kB genome, its capsid contains three viral proteins VP1, VP2 and VP3, with VP1 being the most abundant [12]. With a regulating protein (Agnoprotein) Progressive Multifocal Leucoencephalopathy (PML) pathogenesis is divided into 3 stages: during the first stage the virus behaves as a subclinical infection; during the second stage it remains latent in the genitourinary tract, bone marrow, tonsils, lung, spleen and gastrointestinal tissue [13-17] and during the third stage it presents viral reactivation and dissemination towards the central nervous system. During the second stage, the virus remains latent with a nonpathologic DNA regulatory region (RR) between codifying proteins, called archetype. Genetic material transcription takes place at the two DNA strands. The early region codifies the regulating proteins along with T protein and its variants (T135, T163 and T165). The latter region codifies the capsid proteins and the Agnoprotein [18]. Early genes are responsible for large T and small t antigen codification, and for the transformation, genetic regulation and replication. They codify counterclockwise while nonregulatory region or late genes codify clockwise.

Agnoprotein is a polypeptide which acts as cell proliferation and growth suppressor enabling second stage cell cycle deregulation. The Agnoprotein interacts with T protein to inhibit DNA replication [19]. The infectious cycle starts when JC Virus protein particles bind (SA) sialic acid related Alpha 2 - 6 cell receptors, and 5HT2A serotonin receptors [20]. Virions enter by way of clathrinmediated endocytosis [21].

Later, by way of a still unclear mechanism, viral DNA is transported to the nucleus. Following early viral genome expression, the viral transcription undergoes a series of changes before being carried to the cytoplasm for translation.

The big T antigens, small t antigens and T proteins (T135, T163 y T165) “Figure 1”, are produced after early region transcription translation [22].

Big T antigens initiate viral DNA replication as well as

the posterior activation [23].

Late transcription translation generates the Agnoprotein and the 3-capsid proteins, and then nucleus encapsidation begins. [24].

The JC Virus is activated under different immunocompromised conditions and starts a demyelination process associated to oligodendroglial cells damage, a place where it multiplies and from where it subsequently emerges [25].

Among JC virus related to manifestations we have:

• Classic progressive multifocal and inflammatory Leucoencephalopathy(cPML-iPML) [26].

• Progressive multifocal Leucoencephalopathy associated to immune reconstitution syndrome (PML-IRIS) [27,28].

• Progressive Multifocal Leucoencephalopathy associated to monoclonal antibodies (natalizumab, efalizumab, rituximab) [29-31].

• Virus C related cerebellar granular cells neuropathy (JCVGCN) [32].

• Meningitis (JCM) [33].

• JC virus related Encephalopathy (JCVE) [34].

In general Symptoms tend to vary in relation to the location of the lesions; hemianopsia is one of the most frequent symptoms and it is present in 40% of cases. The patient might also have progressive decrease in muscular strength along with hemiparesis, ataxia and walking difficulties.

Cognitive deterioration is present in progressive manner and may lead to dementia [50].

Seizures may occur during the course of the disease or might be the first manifestation of disease [51].

Several therapeutic regimes have been used to treat PLM and HIV patients with poor results up to now. Some of them involve application of mefloquine [52], cidofovir [53], mirtazapine [54], topotecan (topoisomerase inhibitor), interferon alpha [55] and citrabine [56].

One study with 4 types of antiretroviral medications, including enfuvirtide, suggested a possible increase in survival [57].

Approximately half of patients with HIV and PML survive after the initiation of antiretroviral therapy. However, the previous neurological deficiency may remain [58].

Plasma Exchange and immune absorption have been used on a PLM nonHIV patient [59].

In general, JCV symptomatic neurological expressions tend to increase progressively, not only on account of a larger number of cases involving HIV patients but due to the development of new therapeutic schemes focused on managing diverse pathologies that may affect in different ways the activity of the immune system.

The growing knowledge on JC Virus neural immune behavior patterns enable development of new diagnostic and therapeutic schemes focused on the early stages of the disease, even before related to clinical manifestations appear, taking into account the great current therapeutic limitations, especially PML cases in conjunction with HIV.