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HIV-sensory neuropathy (HIV-SN) is a debilitating complication in HIV patients with or without anti-retroviral treatment (ART). Common symptoms of HIV-SN include pain, decreased sensation, paresthesias, and dysesthesias in a symmetric stocking-glove distribution. While HIV-1 protein such as gp120 is implicated in HIV-SN (e.g. impaired large-diameter fiber), ART itself was recently shown to contribute to HIV-SN in HIV patients and impair thin fiber. Multiple host mechanisms may play roles during the pathogenesis of HIV-SN, including neuron-glia interactions in the spinal dorsal horn (SDH), inflammation, mitochondrial dysfunction and endoplasmic reticulum stress. Concurrent infections, such as tuberculosis, also carry a higher likelihood of HIV-SN as well as environmental or genetic predisposition. Pro-inflammatory cytokines such as IL-1, IL2 receptor-alpha, and tumor necrosis factor (TNF) along with abnormal lactate levels have been identified as potential players within the complex pathophysiology of this condition. In this paper, we review the pathophysiology of HIV neuropathy, focusing on the various treatment options available or under investigation. Although several treatment options are available e.g., the capsaicin patch and spinal cord stimulation, symptomatic control of HIV-SN are often challenging. Alternative approaches such as self-hypnosis, resistance exercise, cannabinoids, and acupuncture have all shown promising results, but need further investigation.

Type 1 diabetes (T1D) is the result of autoimmune-mediated destruction of pancreatic islet β-cells by activated autoreactive inflammatory cells, effecting insulin production from β-cells. The Ca2+-independent phospholipase A2β(iPLA2β), a member of PLA2 family, hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid, which can be metabolized to bioactive lipids. Our work has revealed that iPLA2βactivation shifts macrophage polarization towards an inflammatory phenotype and that inhibition of iPLA2βreduces the development of T1D. We have now identified that iPLA2βactivation induces generation of select pro-inflammatory lipids in the non-obese diabetic (NOD) mice, including prostaglandins (PGs) and DHETs that accompany T1D development. To assess the role of these lipids in T1D development, NOD mice were administered (ip) polyethylene glycol 400 (vehicle), TPPU (sEH inhibitor, 3mg/ml), or PTUPB (dual antagonist of COX2/sEH, 9mg/ml) for up to 30 weeks. Measurement of blood concentrations of TPPU and PTUPB confirmed availability of the inhibitors between dosages. As expected, over the study-period glucose tolerance was impaired in the PEG group. Whereas glucose tolerance was not improved by PTUPB, it was significantly ameliorated by TPPU. These findings suggest that sEH1 inhibition, and thus the production of DHETs, can have beneficial effects in mitigating T1D development. Because different PGs can have pro- or anti-inflammatory effects, they further suggest that inhibition of COX2 may not be as effective as it may also lead to reductions in anti-inflammatory PGs. Overall, our findings support a role for select iPLA2β-derived lipids (iDLs) in T1D development and suggest developing strategies to target iPLA2βor the generation of select iDLs to prevent onset/progression of T1D. Disclosure T. White: None. S. Ramanadham: None. B. Hammock: None. Funding University of Alabama at Birmingham, Iacocca Family Foundation; U.S. Department of Veterans Affairs (BX001792, 13F-RCS-002); National Institutes of Health (R01DK69455, R01DK110292 to S.R.), (R01HL125353), (U01HD087198), (RR031535), (R01AI139072)