Comprehensive analysis of spinal cord inflammatory factors in HIV Tat-induced neuropathy in mice

Despite advancements in HIV treatment, HIV neuropathy, caused by nerve damage following HIV infection, continues to be a major cause of morbidity. Inflammatory responses both in the central and peripheral nervous systems have been implicated as contributing mechanisms, but the role of the HIV protein Trans-Activator of Transcription (Tat) in HIV neuropathy is not well understood. In this study, we report the development of neuropathy-like behavioral changes in doxycycline-inducible HIV Tat transgenic (iTat) mice using comprehensive behavioral assessments. These changes include increased hind paw mechanical sensory sensitivities in both sexes, and increased cold sensitivity and reduced hind paw grip strength predominantly in females. Hind paw skin intra-epidermal nerve fiber (IENF) density showed a small but significant transient increase in the density of CGRP+ fibers at day 21 post-Tat induction in both sexes, while the recovery was faster in females. As Tat is induced primarily in the central nervous system in iTat mice, we therefore focused on elucidating central mechanisms by performing inflammation-targeted RNA profiling in lumbar spinal cord via NanoString assay followed by bioinformatic analysis to identify signaling pathways that may be responsible for the observed symptomatic changes. Three key signaling pathways - apoptosis, inflammation mediated by chemokine and cytokine, and Toll-like receptor signaling pathways - were identified. Subsequent qRT-PCR assays confirmed Tat-induced changes of selected genes. Altogether, we demonstrated that Tat induction is associated with sex-dependent neuropathy-like changes. The concurrent changes in selected inflammation-related signaling pathways within lumbar spinal cord shed light on potential underlying central mechanisms.