What explains HIV -induced pain syndrome?

Does HIV-1 Tat protein induce pain in HIV/AIDS sufferers? Notice a Tat induced increase in activity when compared to control or inactivated protein. (Taken from: Chi, et al, 2011)

Pain is an extremely complicated symptom - just see the TED talk below on chronic pain, yet of the 33.4 million people currently living with HIV/AIDS worldwide, 90% will experience peripheral neuropathy - otherwise known as pain. This a general unrecognised and under-diagnosed (and under-treated) outcome of HIV infection, yet the reasons how and why the viral infection induces this are unknown, but probably are pretty complex.

Is it because of the inflammatory response? The antivirals being taken? Or, the direct effects of virus replication? While the importance of pain as a symptom of HIV/AIDS will only become more evident as this disease is further transformed into a chronic - yet manageable - illness.

HIV-1 genome organisation - one of these genes may be responsible for HIV/AIDS-associated pain. Notice Tat, expressed via splicing. (Wikipedia)

But HIV itself is not known to infect neurons (the major players in pain) during a natural infection, so how could it mess with their activity? One explanation for this is that the virus itself induces pain through interactions with the peripheral nervous system via the infection of a small number of cells associated with neurons (perivascular macrophages, microglia and astrocytes). And, maybe from this site, some effect of virus replication could damage the nearby neuronal cells, especially seeing as a number of HIV-encoded proteins have been shown to have a toxic effect on neurons. The role that these play in pain has not yet been explored.

A paper published this week in PLoS ONE (get paper here) explores the role of HIV-1 Tat protein - a protein released by infected cells and found in patients blood - on the activity of rat dorsal root ganglia neurons, which is a widely used model system for peripheral neurons and pain.

A rat dorsal root ganglion neuron - a model system for mammalian peripheral nervous system and pain. (Rick Stahl, NikonSmallWorld)

This group determined that addition of a recombinant form of tat specifically induced hyper-excitability in a dose dependent manor (independent of viral infection and other HIV proteins). It is believed that hyper-excitability or persistent firing of neurons may be experienced as pain in the sufferer. This effect was traced to a down-regulation of mRNA levels of cdk5 (a regulator of neuron activity) and its activator, p53 while knock-down of cdk5 appeared to induce the same kind of hyper-activity in these neurons. Tat may also induce greater levels of cell-death upon treatment.

The model put forward from this investigation appears to be that following HIV acquisition, the virus infects resident non-neuronal cells among the peripheral nervous system (lying close by to neurons). From here, tat is released into the space surrounding the cells and binds to - and interacts with - the neurons causing excitability and associated pain, and possibly cell death.

To further test if this hypothesis is correct, work will have to be completed with actual HIV and not just addition of tat protein. Cells could be pre-infected with the virus and then added alongside the neurons to see whether secreted, HIV tat functioned the same. Or an in vivo model of tat/neuron interaction could be used. This also gives us some clues as to a possible anti-pain treatment through blocking of Tat activity.

Chi, X., Amet, T., Byrd, D., Chang, K., Shah, K., Hu, N., Grantham, A., Hu, S., Duan, J., Tao, F., Nicol, G., & Yu, Q. (2011). Direct Effects of HIV-1 Tat on Excitability and Survival of Primary Dorsal Root Ganglion Neurons: Possible Contribution to HIV-1-Associated Pain PLoS ONE, 6 (9) DOI: 10.1371/journal.pone.0024412