Background:  Peripheral neuropathy is the most common neurological complication of HIV infection affecting quality of life and effective use of HAART regimens. Recently we developed in vitro models of HIV-associated neuropathies (distal sensory polyneuropathy due to the HIV infection itself and antiretroviral toxic neuropathy due to some of the nucleoside analogue reverse transcriptase inhibitors [NRTI]). We used these models to investigate mechanisms of neuronal injury and more importantly to screen for neuroprotective compounds. However, there are no reliable models of HIV-associated neuropathies in rodents for effective drug screening. In this study, we developed a mouse model of HIV-associated sensory polyneuropathies.

Methods: We administered oral didanosine (ddI) in drinking water of transgenic mice expressing HIV viral envelope protein gp120 under the GFAP promoter, which allows expression in the glial cells. After 1 month, we harvested the distal footpad skin, intrinsic foot muscles, sciatic nerves, and spinal columns for a detailed evaluation of the peripheral nervous system by immunohistochemical and ultrastructural analyses.

Results:  Transgenic mice expressing gp120 in the glial cells, when administered ddI, developed a sensory neuropathy characterized by reduction in intraepidermal unmyelinated small sensory fibers and reduction in the number of small myelinated and unmyelinated fibers in the distal nerves. There was no significant neuronal loss at the DRG level.

Conclusions:  This animal model combines the neurotoxic effects of high levels of gp120 in the endoneurium and exposure to ddI, a NRTI known to cause peripheral neuropathy in patients. Using this animal model we will be able to study pathogenic mechanisms and contribution of each to the axonal degeneration in detail. Furthermore, we will use this animal model to screen for drugs that are promising as neuroprotective agents in our in vitro assays.

Keywords: Neuropathy; ddI; gp120