(227) HIV Sensory Neuropathy Related Behaviors in Doxycycline Inducible HIV-1 Tat Transgenic Mice

Abstract

Peripheral neuropathies are the most frequent neurological complications associated with HIV, within which HIV sensory neuropathy (SN) is the most common form, which affects 30-50% of HIV/acquired immunodeficiency syndrome (AIDS) patients. HIV SN is frequently manifested with hard-to-manage pain and is often under-diagnosed and/or under-treated. Tat, trans-activator of transcription, is a key activator of HIV transcription. Despite that recent studies have highlighted the role of HIV Tat in the pathophysiology of HIV-associated neurocognitive disorders (HANDs), the involvement of HIV Tat in neuropathic pain associated with HIV SN has not been extensively investigated. Our preliminary data showed that both single and repeated intrathecal injection(s) of HIV Tat induced mechanical hypersensitivity. In the current study, we further examined pain and functional related behavioral changes in doxycycline inducible HIV-1 Tat transgenic (iTat Tg) mice following the induction of Tat expression. Two induction regimen were compared: 7-day daily injection vs. 21-day daily injection of doxycycline (i.p. at 100mg/kg). Sensory sensitivities (mechanical, heat and cold) were assessed to evaluate pain-like behaviors. Sensory (pin prick assay) and motor (hind limb grip strength, toe spread reflex and toe spacing score) functional tests were used to evaluate hind paw functions associated with Tat expression. Both regimens induced significant mechanical hypersensitivity and significant reduction of grip strength from day 3 post the initiation of Tat induction to the end of the experiment (day 35) in iTat Tg mice. Tat induction for 21 days also significantly induced cold hypersensitivity in iTat Tg mice up to day 14 post-the first doxycycline injection. Neither regimen induced significant heat hypersensitivity or affected other functional measurements. Together, our results suggest the utility of iTat Tg mice in studying the role of Tat in HIV SN. Sex-depended differences and Tat-induced molecular pathways will be further investigated in future studies. (Grant support: R21 DA044886 [PI Cao])