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<p>Currently, human immunodeficiency virus-1 (HIV-1) spreads around the globe and half of HIV-1-positive individuals suffer from HIV-associated neurocognitive disorder (HAND). HIV-1 infection of astrocytes leads to neuroinflammation and neuronal injury. However, the underlying molecular mechanisms of HIV-1 negative factor (Nef)-mediated astrocytic dysfunction, remain largely unclear. In the present study, our data showed that astrocytic Nef expression facilitated astrocytes proliferation, pro-inflammatory cytokines production and A1-like astrocytes polarization. Mechanistically, Nef-activated NF-κB p65 directly bound to the promoter regions of the proliferative marker (<i>CyclinD1</i>), the inflammatory genes (<i>Il-6</i>, <i>Ccl2</i>, <i>Ccl5</i> and <i>Cxcl10</i>) and the A1-specific marker (<i>C3</i>), and upregulated these genes expression at transcriptional levels. Conversely, NF-κB signaling inhibitor BAY11-7082 (2&#xa0;μM) or RNA interference targeting of NF-κB p65 markedly mitigated astrocytes-mediated Nef neurotoxicity. Moreover, Nef-transduced astrocytes-derived conditioned media induced large amount of apoptotic HT-22 and SH-SY5Y neural cells, which was remarkably reversed in response to NF-κB inhibition. Finally, in animal models, we determined that knockdown of NF-κB p65 effectively ameliorated Nef‑induced neuroinflammation, A1-like astrocytes polarization and neuronal death. Taken together, our data suggest that Nef induces astrocytes proliferation, inflammatory response, A1-like astrocytes polarization and neuronal death in a NF-κB-dependent manner. Our findings propose that NF-κB signaling might be a desirable therapeutic target for relief of astrocytes-mediated Nef neurotoxicity.</p>

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HIV-1 Nef induces astrocytes proliferation, inflammatory response, A1-like astrocytes polarization and subsequent neuronal apoptosis via NF-κB signaling pathway

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Lei Zhang,
  • Huan Yao,
  • Wenhua Tao,
  • Duo Cao,
  • Lin Gao

摘要

Currently, human immunodeficiency virus-1 (HIV-1) spreads around the globe and half of HIV-1-positive individuals suffer from HIV-associated neurocognitive disorder (HAND). HIV-1 infection of astrocytes leads to neuroinflammation and neuronal injury. However, the underlying molecular mechanisms of HIV-1 negative factor (Nef)-mediated astrocytic dysfunction, remain largely unclear. In the present study, our data showed that astrocytic Nef expression facilitated astrocytes proliferation, pro-inflammatory cytokines production and A1-like astrocytes polarization. Mechanistically, Nef-activated NF-κB p65 directly bound to the promoter regions of the proliferative marker (CyclinD1), the inflammatory genes (Il-6, Ccl2, Ccl5 and Cxcl10) and the A1-specific marker (C3), and upregulated these genes expression at transcriptional levels. Conversely, NF-κB signaling inhibitor BAY11-7082 (2 μM) or RNA interference targeting of NF-κB p65 markedly mitigated astrocytes-mediated Nef neurotoxicity. Moreover, Nef-transduced astrocytes-derived conditioned media induced large amount of apoptotic HT-22 and SH-SY5Y neural cells, which was remarkably reversed in response to NF-κB inhibition. Finally, in animal models, we determined that knockdown of NF-κB p65 effectively ameliorated Nef‑induced neuroinflammation, A1-like astrocytes polarization and neuronal death. Taken together, our data suggest that Nef induces astrocytes proliferation, inflammatory response, A1-like astrocytes polarization and neuronal death in a NF-κB-dependent manner. Our findings propose that NF-κB signaling might be a desirable therapeutic target for relief of astrocytes-mediated Nef neurotoxicity.