Establishment of a Rodent Model of HIV-Associated Sensory Neuropathy

Abstract

Human immunodeficiency virus (HIV)-associated sensory neuropathy (SN)is the most common neurological complication of HIV infection in the current highly active antiretroviral therapy era. The painful sensory neuropathy is associated with the use of dideoxynucleoside antiretrovirals, and its development limits the choice of antiretroviral drugs in affected patients. There are presently no effective therapies for HIV-SN, and moreover there has been no robust animal model of HIV-SN in which candidate therapeutic agents can be tested. In this paper, we show that we have established a rodent model of HIV-SN by oral administration of a dideoxynucleoside drug, didanosine, to transgenic mice expressing the HIV coat protein gp120 under a GFAP promoter. The neuropathy in these rodents is characterized by distal degeneration of unmyelinated sensory axons, similar to the "dying back" pattern of C-fiber loss seen in patients with HIV-SN. This model will be useful in examining mechanisms of distal axonal degeneration and testing potential neuroprotective compounds that may prevent development of the sensory neuropathy.

Animal Models of Peripheral Neuropathies

“…These mice develop a slow onset distal axonal degeneration of only the small unmyelinated axons by 15 to 18 months of age. However, this process can be accelerated, and neuropathy can be "unmasked" in young animals given daily didanosine [105]. In this mouse model, there is degeneration of distal axons of unmyelinated fibers, as demonstrated by the reduction of a number of unmyelinated axons in the plantar nerves, but not proximally in the sciatic nerves.…”

“…Prior in vitro studies indicated that HIV envelope protein gp120 can induce indirect neurotoxicity in rat primary DRG sensory neurons [103] and anti-retroviral drugs, especially nucleoside reverse transcriptase inhibitors, which cause degeneration of established DRG neurites [104] mimicking distal axonopathy seen in HIV-SN patients. Combining these observations, we developed a mouse model of HIV-SN that recapitulates the typical features of early stage HIV-SN [105]. In this transgenic mouse model, gp120 is expressed under the GFAP promoter [106], thereby allowing exposure of only the unmyelinated C-fiber axons to gp120, because in the peripheral nervous system myelinated Schwann cells do not express GFAP, but the unmyelinating Schwann cells do.…”

Chemokines and the pathophysiology of neuropathic pain

“…Indeed, Keswani and colleagues have presented a model in which gp120 can act in both these ways (93,97). In the first instance these authors have demonstrated that binding of gp120 to CXCR4 receptors expressed by DRG satellite glial cells up-regulates the release of the chemokine RANTES which can then activate CCR5 receptors expressed by DRG neurons.…”

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

“…* Shangdong Liang liangsd@hotmail.com 1 transcriptase inhibitors may lead to an increased risk of pathological findings [8][9][10]. However, the pathogenesis of HIV distal symmetric polyneuropathy in humans remains poorly understood.…”