Restriction of HSV-1 replication by pistachios (Pistacia vera L.) reveals a promising strategy for regulating virus-mediate chemokine response in THP-1 cells

In recent years, great interest has been committed to the search for alternative clinical treatments for herpetic infections that reduce side effects, overcome drug resistance phenomena, and fight the intense inflammatory response triggered by viral infection. Polyphenols are well-known pharmacologically active compounds with both immunomodulatory and antiviral activity present in large quantities in pistachios ( Pistacia vera L. ). The present work investigates the antiviral properties of pistachio extracts against HSV-1 and their potential immunomodulatory effect on human monocytic cells, with a focus on NF-κB signaling. RT ² profiler PCR array was used to identify differential gene expression levels of chemokines during infection and pretreatment. We discovered that HSV-1 induces a potent activation of cytokines and chemokines in monocytes entirely abrogated by in vitro treatment with pistachio extracts. Our focus included the CXCL10, CXCL11, CCL13, CCL2, CCL4, CCL13 and the receptor CMKLR1, particularly expressed following HSV-1 replication and downregulated upon pistachio extracts pretreatment, we further confirmed this inhibitory activity using zeaxanthin, a bioactive carotenoid found in pistachios, previously shown to inhibit HSV-1 replication in permissive cells. In addition, by blocking viral replication with phosphonoacetic acid, we demonstrated that in HSV-1-infected THP-1 cells, the activation of CXCL10, CXCL11, CCL13, CCL2, CCL4, CCL13 and the receptor CMKLR1, was wholly abrogated, suggesting that chemokine activation is strictly dependent on active HSV-1 replication. Lastly, using THP-1-dnIκBα cells, we have demonstrated that chemokine accumulation was correlated with HSV-1-induced NF-κB activation. This study highlights the use of pistachio extracts and zeaxanthin as a promising therapeutic approach against HSV-1. Notably, it offers valuable insights into the complex virus-host interaction, demonstrating how HSV-1 modulates the cell response mediated by chemokines, such as CXCL10, CXCL11, CCL13, CCL2, and CCL4, and the receptor CMKLR1, to maintain a delicate balance with the host cell, thereby promoting viral persistence.