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Mechanism and role of astrogliosis in the pathogenesis of HIV-associated pain One Sentence Summary: Neuron-to-astrocyte Wnt5a signaling-activated astrogliosis is essential for the development of pathological pain induced by HIV-1 gp120

Pathological pain is the most common neurological disorder in people living with HIV-1/AIDS (PLWHA), and rationale-based effective treatment is not available. Multiple neuropathologies develop in the pain transmission pathways in of HIV patients, consistent with their nociceptive dysfunction1,2. One of the prominent neuropathologies associating with the manifestation of pain in HIV patients is astrogliosis (a.k.a. reactive astrocytes) in the spinal dorsal horn (SDH)1, the spinal center for the transmission of pain signals from peripheral organs to the brain. However, the pathogenic role and the activation mechanism of astrogliosis are unclear. Here, we show that the astrogliosis is crucial for the pain pathogenesis induced by HIV-1 gp120, a key etiologically relevant protein2, and that a neuron-to-astrocyte Wnt5a signal controls the astrogliosis. We found that ablation of astrogliosis blocked the development of gp120-induced mechanical hyperalgesia, and concomitantly the expression of neural circuit polarization (NCP) in the SDH. In addition, we demonstrated that conditional knockout (CKO) of either Wnt5a in neurons or its receptor ROR2 in astrocytes abolished not only gp120-induced astrogliosis but also the hyperalgesia and the NCP. Furthermore, we found that the astrogliosis promoted expression of the NCP and the hyperalgesia via IL-1β regulated by a Wnt5a-ROR2-MMP2 axis. Our results elucidate an important role and a novel mechanism of astrogliosis in the pathogenesis of HIV-associated pain. Targeting reactive astrocytes by manipulating the mechanistic processes identified here may lead to the development of effective therapy to treat the pain syndrome in HIV patients.