SIV-Induced Immune Activation and Metabolic Alterations in the Dorsal Root Ganglia During Acute Infection

Abstract

Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) remains a frequent neurologic complication of HIV infection. Little is known about alterations in the peripheral nervous system during the early stages of HIV, a time when neuroprotective interventions may be most beneficial. We performed Nanostring gene expression analysis on lumbar dorsal root ganglia (DRG) from 6 simian immunodeficiency virus (SIV)-infected pigtailed macaques killed at 7 days post-inoculation and 8 uninfected controls. We found significant upregulation of many genes involved in immune signaling and activation in the DRG. Among genes related to glutamate metabolism, there was significant upregulation of glutamine synthetase (GS), while glutaminase (GLS) was downregulated. Several genes involved in the oxidative stress response also showed significant differential regulation in the DRG of 7d SIV-infected animals, with superoxide dismutase-2 (SOD2) showing the greatest median fold change compared to controls. Novel findings in the DRG were compared to corresponding brain data and further investigated at the protein level by Western blotting and immunohistochemistry. Together with our previous finding of significant epidermal nerve fiber loss at 14 days post-SIV infection, results of this study demonstrate that immune activation and altered cellular metabolism at in the DRG precede and likely contribute to early sensory nerve injury in HIV-SN.

Intraepidermal Nerve Fiber Analysis in Human Patients and Animal Models of Peripheral Neuropathy: A Comparative Review

“…Pigtailed macaques (Macaca nemestrina) inoculated with both an immunosuppressive SIV strain and a neurovirulent SIV clone develop striking IENF loss in the distal limbs that begins early in the course of infection (14 days postinoculation) and is associated with evidence of macrophage activation in the lumbar dorsal root ganglia. 3,73,74 Similar findings have also been reported in CD8þ T-cell-depleted rhesus macaques (Macaca mulatta) infected with SIV-mac251. 7,8 In the dual SIV-inoculated pigtailed macaques, significant IENF loss was detectable earlier than decreased conduction velocity in the sural nerve, showing it to be a more sensitive indicator of small nerve fiber damage in this model.…”

Emerging importance of satellite glia in nervous system function and dysfunction

“…Infection with simian immunodeficiency virus is a useful model to study HIV. In macaques infected with simian immunodeficiency virus there was an upregulation of GFAP in DRG SGCs 125 , but its contribution to the disease is not known. Another virus family is coronavirus that includes MERS-CoV, SARS-CoV and SARS-CoV-2 (which causes COVID-19), which are highly infective and can be fatal in humans.…”

Combining In Vivo Corneal Confocal Microscopy With Deep Learning–Based Analysis Reveals Sensory Nerve Fiber Loss in Acute Simian Immunodeficiency Virus Infection

“…These data demonstrate the ability of the combination of IVCM and automated analysis to detect corneal nerve fiber loss during acute infection, an early timepoint when SIV replicates in sensory ganglia macrophages and induces both immune activation and metabolic alterations. (4,7,24) Similar to corneal nerve fiber length, fractal dimension also declined with SIV infection with 10 of the 12 animals with lower counts after SIV infection (Figure 7; P = 0.008, paired t-test). In contrast, corneal nerve fiber tortuosity was not significantly altered during acute infection and this may not be a sensitive marker of relatively acute damage.…”

“…(19) Studies of both pigtailed macaques (Macaca nemestrina) and rhesus macaques (Macaca mulatta), for example, have been highly informative for understanding HIV pathogenesis including peripheral nerve damage that underlies development of HIV sensory neuropathy. (4)(5)(6)(7)(24)(25)(26) The current clinical standard for measuring sensory nerve . CC-BY-NC-ND 4.0 International license available under a was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”