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.

Figure 1.

Oral administration of the antiretroviral drug DDI to gp120 transgenic mice induces cutaneous denervation. DDI administration to gp120 transgenic mice resulted in a decreased IENF density (p < 0.05) in the plantar footpads of gp120 transgenic mice. A, Representative PGP 9.5-stained skin biopsies from the plantar footpads of gp120 transgenic mice with and without DDI exposure. The black arrows show individual IENFs, and the yellow dots highlight the dermal–epidermal junction. B, Quantitation of plantar footpad IENF densities for wild-type and gp120 transgenic mice ± DDI exposure. Note that in contrast to gp120 transgenic mice, DDI exposure to age-matched wild-type controls did not reduce IENF density. In addition, there was no significant difference in IENF density between wild-type controls and gp120 transgenics not exposed to DDI. n = 8 animals per group; p < 0.05 compared with other groups.

Figure 2.

Administration of DDI to gp120 transgenic mice induces loss of unmyelinated axons in distal plantar nerves. A, Representative electron micrographs of Remak bundles from the distal plantar nerves from gp120 transgenic mice ± DDI exposure are shown. Normal Remak bundles containing unmyelinated axons are seen in mice not given DDI (small arrow). In DDI-treated mice, “empty” Remak bundles (i.e., Schwann cells devoid of unmyelinated axons) (large arrow) are seen. B, In mice given DDI, Remak bundles contain fewer unmyelinated axons (i.e., the histogram is shifted to the left). p < 0.05; n = 8 animals per group.

Figure 3.

DDI administration does not induce axonal degeneration in the proximal sciatic nerve. A, Plastic sections of proximal sciatic nerve from wild-type and gp120 transgenic mice with and without exposure to DDI revealed no abnormalities. In particular, no evidence of Wallerian-like degeneration was observed, with similar staining patterns for myelinated axons. B, Histograms of unmyelinated axons showed similar patterns, suggesting that there was no significant unmyelinated axonal loss proximally. C, Mean number of unmyelinated axons per Remak bundle are shown (n = 4–6 animals per group). WT, Wild-type.

Figure 4.

Thermal sensation and motor strength in gp120 transgenic mice treated with DDI. A, Paw withdrawal latency to thermal stimulation was done at baseline and after 4 weeks of oral DDI treatment. Only DDI-treated gp120 transgenic mice developed thermal hyperalgesia. *p < 0.05 compared with gp120 transgenic mice. B, Motor function using grip strength testing was done at baseline and after 4 weeks of oral DDI treatment. In both graphs, the results are expressed as a percentage change from the baseline. Gray bars denote baseline, and black bars represent repeat testing after 4 weeks of DDI or control. Error bars indicate SE.