[5] The virus causes leukoencephalopathy and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with immunosuppressive drugs (e.g. in organ transplant patients).

In addition, recent studies suggest that this virus may latently infect the human semen[11] as well as the chorionic villi tissues.

[13] Human polyomavirus 2 can cross the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor.

It is thought that these differences in promoter sequence contribute to the fitness of the virus in the CNS and thus to the development of PML.

[6] Certain transcription factors present in the early promoter sequences of Human polyomavirus 2 can induce tropism and viral proliferation that leads to PML.

[16] The protein encoded by these early sequences, T-antigen, also plays a key role in viral proliferation,[17] directing the initiation of DNA replication for the virus as well as performing a transcriptional switch to allow for the formation of the various capsid and regulatory proteins needed for viral fitness.

Further research is needed to determine the exact etiological role of T-antigen, but there seems to be a connection to the early initiation of the active virus from its archetypal dormant state.

[18] Several studies since 2000 have suggested that the virus is also linked to colorectal cancer, as Human polyomavirus 2 has been found in malignant colon tumors, but these findings are still controversial.

[19] Although Human polyomavirus 2 infection is classically associated with white matter demyelination and PML pathogenesis, recent literature has identified viral variants as etiological agents of other novel syndromes.

[citation needed] Human polyomavirus 2 also appears to mediate encephalopathy, due to infection of cortical pyramidal neurons (CPN) and astrocytes.

The precise molecular mechanisms mediating Human polyomavirus 2 meningeal tropism remain to be found.

[22][23][24] It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection.