Sood Vikas, Lata Sneh, Ramachandran Vishnampettai G, Banerjea Akhil C
Department of Microbiology, University College of Medical Sciences and GTB Hospital, New Delhi, India.
Virology Lab II, National Institute of Immunology, New Delhi, India.
Front Microbiol. 2019 Jan 31;10:114. doi: 10.3389/fmicb.2019.00114. eCollection 2019.
Human Immunodeficiency Virus-1 (HIV-1) is known to induce the expression of SOCS3 which is a negative feed-back regulator of inflammatory responses. Here, we demonstrate that reactivation of latent HIV-1 leads to degradation of SOCS3 at early time points. Interestingly, SOCS3 degradation following transfection of HIV-1 RNA as well as polyIC in THP-1 cells further confirmed the role of viral RNA signaling in SOCS3 biology. Degradation of SOCS3 contributes toward viral RNA induced inflammatory responses. NF-κB signaling is also induced upon HIV-1 infection which leads to the production of pro-inflammatory cytokines to control the viral spread. Further investigations revealed that SOCS3 inhibits the expression and activity of p65 by interacting with it and inducing its ubiquitin-dependent proteasomal degradation. SH2 domain was critical for SOCS3-p65 interaction and p65 degradation. We also found that expression of SOCS3 promotes HIV-1 replication. Thus, HIV-1 downregulates SOCS3 in early phase of infection to promote inflammatory responses for large production of activated cells which are suitable for viral spread and induces SOCS3 later on to limit inflammatory responses and ensure viral survival.
已知人类免疫缺陷病毒1型（HIV-1）可诱导细胞因子信号转导抑制因子3（SOCS3）的表达，SOCS3是炎症反应的负反馈调节因子。在此，我们证明潜伏HIV-1的重新激活在早期会导致SOCS3的降解。有趣的是，在THP-1细胞中转染HIV-1 RNA以及聚肌胞苷酸（polyIC）后SOCS3的降解进一步证实了病毒RNA信号在SOCS3生物学中的作用。SOCS3的降解有助于病毒RNA诱导的炎症反应。HIV-1感染还会诱导核因子κB（NF-κB）信号传导，从而导致促炎细胞因子的产生以控制病毒传播。进一步的研究表明，SOCS3通过与p65相互作用并诱导其泛素依赖性蛋白酶体降解来抑制p65的表达和活性。SH2结构域对于SOCS3与p65的相互作用及p65的降解至关重要。我们还发现SOCS3的表达促进HIV-1复制。因此，HIV-1在感染早期下调SOCS3以促进炎症反应，从而大量产生适合病毒传播的活化细胞，并在后期诱导SOCS3以限制炎症反应并确保病毒存活。
