Gaining entry to the CNS

The human JC polyomavirus (JCV) is estimated to be present in 70–80% of the adult population, and in healthy people it is generally tolerated without ill effects. However, in immunocompromised individuals — in particular, patients with AIDS — it can cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease. At present, this devastating condition cannot be treated, but a recent report in Science indicates that serotonin (5-hydroxytryptamine or 5-HT) receptor antagonists could provide a new therapeutic approach.

PML results from infection of oligodendrocytes by JCV, so how does the virus gain entry to these cells? From a series of in vitro experiments, Elphick and colleagues obtained several pieces of evidence to indicate that it latches on to 5-HT receptors. It has previously been shown that glia can be rendered resistant to JCV infection by certain drugs of the serotonin–dopamine inhibitor (SDI) class. Elphick et al. showed that dopamine-receptor-specific drugs were considerably less effective at blocking JCV infection than drugs that inhibited both dopamine and 5-HT receptors, so they focused their attention on the 5-HT receptors.

The authors found that JCV infection of glial cells could be inhibited by 5-HT_2A-receptor (5-HT_2AR) antagonists or anti-5-HT_2AR monoclonal antibodies. In the reverse experiment, they asked whether 5-HT_2AR could confer susceptibility to JCV infection on cells that do not normally express this receptor. The 5-HT_2AR-negative HeLa cell line is usually resistant to JCV infection, but when these cells were transfected with a 5-HT_2AR-expressing construct, they could be readily infected by JCV.

Further evidence that JCV uses 5-HT_2AR as an entry point came from the observation that the internalized viral particles co-localized with 5-HT_2AR in glial cells. However, 5-HT receptors are not the only factors that determine a cell's vulnerability to JCV infection. For example, 5-HT receptors are widely expressed in neurons, yet these cells do not normally become infected by JCV. It was previously shown that α2,6-linked sialic acid is an important component of the JCV receptor, and this monosaccharide is displayed on the surface of glia but not neurons. HeLa cells express α2,6-linked sialic acid but not 5-HT receptors, so they can bind JCV but cannot internalize the virus. So, a model for JCV infection can be envisaged, in which the virus is captured on the cell surface by α2,6-linked sialic acid, and is subsequently internalized through an interaction with 5-HT receptors.

5-HT-receptor antagonists are already used to treat many neurological and psychiatric disorders, so if these new in vitro findings can be recapitulated in vivo, these drugs could represent a ready-made source of therapeutic agents for treating PML. Elphick et al. suggest two approaches: the drugs could be used to prevent JCV from entering the CNS in HIV-infected individuals, or to limit further demyelination in patients who have already developed PML.