HIV Tat-associated Sensory Neuropathy and the Contribution of Toll-like Receptor Pathway

总结

Summary Peripheral neuropathies are the most frequent neurological complications associated with HIV, within which HIV sensory neuropathy (HIV-SN) is the most common form, affecting nearly half of HIV/AIDS patients with the prevalence ranging from 1.2 – 69.4%. HIV-SN frequently manifests with hard-to-manage pain and is often under-diagnosed and/or under-treated, yet, the large variation in prevalence does not allow for detection of significant differences in prevalence between HAART-exposed vs. HAART-non-exposed individuals. There is no specific FDA-approved treatment for HIV-SN. Tat, trans-activator of transcription, a regulatory protein among the first proteins expressed following HIV infection, is a key activator of HIV transcription and can affect both HIV infected cells and non-infected neighboring cells via its secretion by infected cells. Although human studies are lacking, recent animal studies using two models of doxycycline-inducible HIV-1 Tat transgenic (iTat) mice from our lab and others provided convincing evidence that HIV Tat contributes to the development of HIV-SN. Therefore, in this proposal, we will further investigate the underlying mechanisms of Tat-associated SN. Our preliminary study identified potential regulation of Tat of Toll-like receptor (TLR) signaling pathway. Given the widely accepted involvement of TLR pathway in neuropathic pain and surprising lack of studies exploring the role of TLR pathway in HIV-SN, we will focus on TLR pathway in Tat-associated SN in this study. We will take advantage of bioinformatic tools to identify FDA-approved drugs without significant interactions with existing antiretroviral drugs that could potentially reverse Tat-induced changes in TLR pathway, and then test their effectiveness in treating Tat-associated SN in vivo. Altogether, we hypothesize that TLR signaling pathway is involved in the development of HIV-Tat-associated SN and it is possible to identify potential treatment for HIV-SN by examining existing drugs via a combined bioinformatics and pre-clinical model approach. This will be tested through 2 Specific Aims. Aim 1 will determine the contribution of Tollip (a key regulator of TLR pathway)-regulated TLR pathways in HIV Tat-associated SN using genetically modified animal models in combination with behavioral and physiological tests. Aim 2 will identify potential drugs for HIV-SN by targeting TLR pathway via a combined bioinformatics and pre-clinical model approach. If successful, we will fill in the knowledge gaps regarding Tat-associated SN and TLRs’ role in HIV-SN. Our comprehensive combination drug discovery strategy will help identify potential drugs for HIV-SN, which can be further tested in other animal models before clinical assessment. Throughout the process, we will prioritize drug candidates that are mechanistically-sound, and potentially easily accessible to all patients.