Figure 4. Possible chemokine receptor function in the context of HIV-1 neuropathy.

The viral coat protein gp120 can bind to the chemokine (CC motif) receptors CCR5 and CXCR4 and can also act as an agonist or antagonist of chemokine action, depending on the circumstances⁹⁴. For example, gp120 can directly excite cultured dorsal root ganglia (DRG) neurons in a similar mode to chemokines and direct injection of gp120 into the rat paw produces allodynia (FIG. 2)⁵⁰. In addition, prolonged treatment of DRG neurons with gp120 produces apoptosis⁹⁵. Therefore, gp120 might induce some features of HIV-1 neuropathy through direct effects on chemokine receptors that are expressed by DRG neurons. It has also been suggested that gp120 could produce effects through the activation of CXCR4 receptors expressed by Schwann cells⁸⁹,¹⁴⁵. According to one hypothesis, activation of these receptors by gp120 causes Schwann cells to secrete the chemokine RANTES (regulated on activation, normal T cell expressed and secreted). RANTES can then activate CCR5 receptors expressed by DRG neurons, which could produce pain through direct excitation⁸⁹. RANTES can also stimulate tumour-necrosis factor-α (TNFα) production by DRG neurons⁸⁹. TNFα might then act in a cell-autonomous manner to produce excitation and pain or neuronal apoptosis¹²⁰. Interestingly, TNFα also suppresses the expression of CXCR4 receptors by Schwann cells and is toxic to these cells. So, it seems that HIV-1 could trigger painful neuropathies in several ways, ranging from the overall consequences of neuroinflammation to the viral-induced activation of chemokine-receptor-induced events in neurons and glia. TNFR, tumour-necrosis factor receptor.