Figure 1: A, Three distinct sites of origin of HIV-related distal sensory polyneuropathy (HIV-DSP) are also the targets for a novel pharmaceutical therapy: (1) sensory nerve endings (distal axons) in skin (particularly feet), (2) dorsal root ganglion (DRG) with DRG neuron (DRGN) cell bodies of distal axons, (3) spinal cord and other central neural circuits, particularly in the somatosensory cortex. B, HIV-infected macrophages release viral coat protein (Vpr) that acts on DRGN/axons to mimic HIV-DSP symptoms, e.g. distal axon loss, allodynia and chronic pain. Potential targets of Vpr actions are cytosolic Ca2+ homeostasis, mitochondria or (Schwann cell) glial cells. We showed that p75 neurotrophin receptor (p75ntr) antagonism blocked Vpr-induced axon inhibiting effects on DRGN.