Abstract
Abstract HIV sensory neuropathy (HIV-SN) affects 30–50% of patients infected with HIV. The role of Tat in HIV-SN has not been studied extensively. Previously, using the doxycycline (DOX) inducible HIV-1 Tat transgenic (iTat) mice, we showed that Tat expression induced neuropathy-like behaviors. Here, we further investigated the role of inflammatory responses within dorsal root ganglia (DRG) and lumbar spinal cord in the development of peripheral neuropathy. To induce Tat expression, DOX was given to iTat mice daily (i.p.) for 14 days. Lumbar spinal cord and DRG tissues were collected at days 0 (no injection), 3, 7, 14, 21, 28 and 35 following the initial injection of DOX. Vehicle control mice received pH-matched phosphate-buffered saline injections. qRT-PCR was performed with DRG tissues. Tat expression induced either transient or progressive upregulation of RNA levels of CCL2, CCL3, CCL4, CCL5, CXCL10, and IL-1beta. Lumbar spinal cord tissues underwent NanoString RNA analysis using a panel of 200+ inflammation-related genes. The patterns of the changes of these genes over time were clustered via the Short Time-series Expression Miner program. Out of the 4 patterns identified, the most significant one was a cluster of genes that were downregulated over time upon Tat induction. Gene ontology term enrichment analysis of this gene cluster via the PantherGo tool further identified a set of genes (IL-6, MAPK2K4, IL-10, HRAS1, BCL2L1, RHOA, JUN, and CREB1) that prevent/inhibit neuronal cell death/apoptosis. In all, both upregulation of selected pro-inflammatory cytokines within DRG, and down regulation of inflammation-related, neuronal survival genes within the spinal cord, could contribute to Tat-mediated peripheral neuropathy.
Published Version
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