Editors' ChoiceAIDS/HIV

The Virus in the Machine

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Science Translational Medicine  10 Nov 2010:
Vol. 2, Issue 57, pp. 57ec175
DOI: 10.1126/scitranslmed.3001884

Patients with HIV enjoy much longer lives now, a benefit of combination antiretroviral therapy. The downside of this longevity is that there is time for various clinical sequelae to emerge. One of these—HIV-associated neurological disease or HAND—confers significant morbidity. HAND often affects the brain's nigrostriatal system, which uses dopamine as a neurotransmitter, is critical to proper movement, and is the brain circuit affected in Parkinson's disease. Perry and colleagues have now identified some of the cast of players that disrupt the nigrostriatal system in HAND.

Using primary cultures of rat midbrain (where the substantia nigra is located), the authors studied the effects of the HIV-1 neurotoxin transactivating factor (Tat). Tat increased the binding capacity of the dopamine transporter (DAT), which normally terminates dopamine signaling by removing it from the synapse. Dopamine acts on dopamine receptors in the midbrain to control physical movement. The enhanced transporter binding of dopamine was a result of an apparent increase in DAT trafficking to the neuronal cell membrane rather than an increase in the total amount of DAT protein. The authors also saw more DAT in the midbrain in a Tat-expressing transgenic mouse, a result consistent with findings in postmortem brains of AIDS patients with HAND. These Tat-induced increases in DAT were abolished by inhibitors of each of the following molecules that are required for the effects of Tat: ryanodine receptors, which regulate intracellular calcium release; calpains, which are ubiquitous calcium-activated proteases involved in numerous cell processes and implicated in neurodegeneration; and glycogen synthase kinase 3β, which is activated by calpains and mediates Tat neurotoxicity. These results thus suggest a cellular pathway for HIV-related neurotoxic effects on the nigrostriatal system.

The authors propose that HIV harms the brain by causing bioenergetic stress, leading to auto-oxidative dopamine neurotoxicity. This process could alter synapses or ultimately kill dopaminergic neurons. Taken together, these findings provide hope for patients, for several potential targets may be found in this proposed chain of events to remediate the disrupted machinery of movement.

S. W. Perry et al., Human immunodeficiency virus-1 Tat activates calpain proteases via the ryanodine receptor to enhance surface dopamine transporter levels and increase transporter-specific uptake and Vmax. J. Neurosci. 30, 14153–14164 (2010). [Abstract]

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