Pathogenesis of HIV-associated sensory neuropathy

PROJECT SUMMARY Sensory neuropathy (SN) is the most common comorbidity in Human Immunodeficiency Virus-1(HIV-1) infected-patients (hHIV-SN), which affects 60% of the 37.9 million HIV infected patients in this world. hHIV-SN is particularly resistant to existing pain relief therapies and now there is no FDA approved HIV specific analgesic available due to poorly understanding of the hHIV-SN pathogenesis. In order to develop disease- specific and mechanism-based therapeutics for hHIV-SN, we must fully elucidate the underlying mechanisms. Healthy skin is mainly innervated by nociceptors labeled by protein gene product 9.5 (PGP9.5+) to generate nociception and the degeneration of PGP9.5+ nociceptor is a critical pathological mark of hHIV-SN. Growth associated protein (GAP43) labels the newly sprouted nociceptor (GAP43+). PGP9.5+ and GAP43+ nociceptors have distinctly neurotrophic dependency on glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) respectively and the expression of GDNF and NGF are regulated by Wnt5a. Wnt5a is a secreted signaling protein in the Wnt family that plays an important role in axonal remodeling and is also specifically up- regulated in the spinal cord of HIV-SN patients with chronic pain. Our publication reported that gp120, an envelope glycoprotein of HIV-1, plays a causative role in neuropathic pain occurred both in gp120-induced mouse SN (mHIV-SN) and in hHIV-SN patients. The gp120-caused aberrant activation of neuronal Wnt5a in sensory neuron and in spinal cord are intimately relevant with the development of SN-associated pain in mouse and in HIV-infected patients as well. Importantly, our preliminary data have shown that Wnt5a-specific antagonist, Box5, blocks mHIV-SN-associated pain and pathologies. Interestingly, in both of the mHIV-SN and hHIV-SN, as PGP9.5+ nociceptor degeneration progresses, even close to the point of denervation, chronic pain remains or worsens, instead of resolving. This phenomenon indicates that the chronic pain in HIV-SN must be mediated by an alternate novel nociceptor, the sprouted GAP43+ nociceptor which specifically mediates the HIV-Associated chronic pain. Our central hypothesis is: HIV-1 gp120 causes mHIV-SN by activation of Wnt5a- NGF mediated sprouting of the GAP43+ nociceptor, which in turn specifically mediates HIV associated chronic pain. We will test this hypothesis by using mHIV-SN mouse model in three Aims. In Aim #1, we will fully investigate the interplay of the sprouting of GAP43+ nociceptors and the degenerating of PGP9.5+ nociceptor in mHIV-SN by using multiple engineering mouse models. In Aim #2, we will determine that gp120-induced the sprouting of GAP43+ nociceptor is mediated by Wnt5a-NGF pathway by pharmacological and genetic approaches. In Aim #3, we will determine the therapeutic potential of antagonisms of Wnt5a by its antagonist, Box5, NGF antagonism by tanezumab and GDNF to treat mHIV-SN in the gp120 mHIV-SN mouse model. Results from this research will shed light on the essential mechanisms of HIV-SN and illustrate the therapeutic potential of Wnt5a-NGF-GAP43 sprouting-based approaches for treating HIV-SN.