Animal Models of HIV Peripheral Neuropathy

Abstract

The use of animal models in the study of HIV and AIDS has advanced our understanding of the underlying pathophysiologic mechanisms of infection. Of the multitude of HIV disease manifestations, peripheral neuropathy remains one of the most common long-term side effects. Several of the most important causes of peripheral neuropathy in AIDS patients include direct association with HIV infection with or without antiretroviral medication and infection with opportunistic agents. Because the pathogeneses of these diseases are difficult to study in human patients, animal models have allowed for significant advancement in the understanding of the role of viral infection and the immune system in disease genesis. This review focuses on rodent, rabbit, feline and rhesus models used to study HIV-associated peripheral neuropathies, focusing specifically on sensory neuropathy and antiretroviral-associated neuropathies.

Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy

“…10 Transgenic mice expressing gp120 have failed to develop PN after 2 months. 11 However, in a murine immunodeficiency virus model 12 and after perineural application of gp120 to the sciatic nerve in rats, 13 peripheral nerve damage has been shown.…”

“…14,15 SIV is particularly attractive given the similarities between humans and nonhuman primates, with SIV being closely related to HIV genomically, structurally, and clinically. 10,16 Both viruses target the CD4 þ lymphocytes, monocytes, and macrophages through CD4 and CCR5, resulting in immune suppression and neuropathology that includes a decline in IENFDs and similar pathology in the DRG. 10 By using a neurovirulent clone and immunosuppressive SIV swarm in pigtailed macaques, Mankowski and colleagues demonstrated that the SIV þ cells in the DRG were CD68 þ macrophages and that damage to the DRG precedes loss of nerve fibers in the skin.…”

“…10,16 Both viruses target the CD4 þ lymphocytes, monocytes, and macrophages through CD4 and CCR5, resulting in immune suppression and neuropathology that includes a decline in IENFDs and similar pathology in the DRG. 10 By using a neurovirulent clone and immunosuppressive SIV swarm in pigtailed macaques, Mankowski and colleagues demonstrated that the SIV þ cells in the DRG were CD68 þ macrophages and that damage to the DRG precedes loss of nerve fibers in the skin. 17e19 We have previously demonstrated that CD8 þ lymphocyte-depleted, SIV-infected rhesus macaques rapidly develop AIDS and histopathology that reproduces the hallmarks of human HIV infection preantiretroviral therapy, including SIV encephalitis, lymph damage, the depletion of gut T cells, and PN.…”

Applications of the FIV Model to Study HIV Pathogenesis

“…Since then, there have been a number of reports providing evidence for predicted RNA and protein products from the minus strand in HIV-1 [93][94][95][96][97][98][99][100][101][102], SIV [103], FIV [104], and in the deltaretrovirus, BLV [105]. The use of neurovirulent strains of FIV has also allowed for the investigation of neuropathogenic effects on the peripheral nervous system (PNS) as a model of HIV distal symmetric polyneuropathy (DSP), demonstrating rapid onset of peripheral neuropathy in FIV infected cats with axonal injury, macrophage activation, and detection of virus within the nerve [50,132]. Indeed, FIV infection results in pathological events in the PNS that are very similar to HIV, including increased numbers of CD3+…”

“…Neurologic disease is an important manifestation of FIV infection, and affected cats may present with either central nervous system (CNS) or peripheral nervous system (PNS) involvement [14,17,18,50,51]. In the PNS, FIV induces significantly increased numbers of CD3+ T cells and macrophages in dorsal root ganglia, and infected cats exhibit pronounced changes in epidermal nerve fiber densities [50,52]. FIV enters the CNS during the acute stages of infection and is present within the brain and cerebral spinal fluid [14,17,53].…”