Changes in genes in the TLR signaling pathway within the lumbar spinal cord of doxycycline-inducible Tat transgenic mice following Tat induction 2254518

Abstract

Abstract Introduction A common complication of human immunodeficiency virus (HIV)-1 infection is HIV neuropathy, which is often associated with poorly managed pain. The toll-like receptor (TLR) pathway is known to be involved in neuropathic pain, but its role in painful HIV neuropathy has not been investigated extensively. Tat, trans-activator of transcription, is a viral regulatory protein expressed early during HIV infection and is a key activator of HIV transcription. Following Tat induction, the glial fibrillary acidic protein (GFAP)-driven, doxycycline-inducible HIV-1 Tat transgenic (iTat) mice display neuropathy-like behaviors. A panel of approximately 200 inflammation-related genes were measured in the lumbar spinal cord of iTat mice following Tat induction via NanoString® technologies. Bioinformatic analysis identified the regulation of Tat of the TLR signaling pathway. Methods In this current study, we further examined the temporal changes of TLR-related genes within the NanoString profiling data to explore the potential involvement of TLR-mediated pathways. Genes encoding TLRs 1-9, major TLR pathway related signaling molecules, type 1 interferons, as well as the interferon-inducible proteins, were analyzed. Tat induction was achieved by treating iTat mice daily with doxycycline from days 0-13. Results We observed that of all the TLRs, TLR3 showed a significant upregulation starting from day 21, while upregulation of both TLRs2, 4 and 9 were slight and/or transient. Transient upregulation of type I interferon genes, as well as several interferon-inducible proteins, such as Ifi44, Ifit1/3, Mx1, and Oas1a, was also noted. No significant sex differences were noted for any of the genes examined. Conclusion Our results indicate an overall upregulation of TLR-mediated type I interferon responses following Tat induction. Ongoing study will determine if these changes are reflected at protein levels. The role of Type I interferon response in Tat-associated neuropathy will be further investigated in the future. Funding Source NIH/NIDA 1R21DA044886 (Cao) and NIH/NINDS 1R01NS132674 (PI Cao) Topic Categories Immune Mechanisms of Human Disease (HUM)