A novel subtype of astrocytes critical for HIV-associated pain pathogenesis

Pathological pain is a frequent complication in HIV patients, yet the underlying mechanism remains elusive, and effective therapeutic targets have not been identified. Reactive astrocytes are specifically activated in the spinal dorsal horn (SDH) of HIV patients with pathological pain and required for HIV-associated pain development in mouse models. These findings suggest that reactive astrocytes play a crucial role in the pathogenesis of HIV-associated pain. However, due to the heterogeneity of reactive astrocytes, the pathogenic subtype remains unknown. In this study, we used single-nucleus RNA-seq (snRNA-seq) transcriptomic analysis to identify a novel subtype of HIV-pain-associated astrocytes (HIPAs) in the lumbar spinal cord of HIV-1 gp120 transgenic models and in the spinal cord of HIV patients. HIPAs express galectin 3 (Gal3) and exhibit transcriptomic signatures of phagocytosis and inflammation. We demonstrated that HIPAs phagocytose neuronal components and are associated with neuronal degeneration. We also found that knockout (KO) of Gal3 in gp120 transgenic mice reduced the number of HIPAs. Furthermore, Gal3 KO inhibited the expression of mechanical allodynia and HIV pain-related pathogenic processes, including neuronal degeneration and neuroinflammation, in gp120 transgenic mice. Our data collectively suggest that HIPAs are a novel Gal3-expressing astrocytic subtype that plays a critical role in gp120-induced pathogenesis in the spinal pain neural circuit. Targeting HIPAs may provide a potential therapeutic strategy for treating HIV-associated pain. Overall design: All cell types from the lumbar spine of wild-type, gp120Tg, gal3KO, and gp120Tg/gal3KO mice were isolated and analyzed using snRNAseq