Restriction of HSV-1 replication by Pistacia vera L. extracts reveals a promising strategy for regulating virus-mediated chemokine response in monocytic 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, and combat the intense inflammatory response triggered by viral infection. Pistachios (Pistacia vera L.) are known to contain polyphenols, pharmacologically active compounds with both immunomodulatory and antiviral activities. 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. The RT2 Profiler PCR array was used to identify differential expression of chemokines during infection and pretreatment. We discovered that HSV-1 induces potent cytokine and chemokine activation in monocytes, and that this activation is significantly reduced by in vitro treatment with pistachio extracts. Our focus included CXCL10, CXCL11, CCL13, CCL2, CCL4, CCL13 and the receptor CMKLR1, which were particularly expressed after HSV-1 replication and downregulated by pretreatment with pistachio extracts. We further confirmed this inhibitory activity using zeaxanthin, a bioactive carotenoid found in pistachios, which has previously shown to inhibit HSV-1 replication in permissive cells. In addition, by blocking viral replication with phosphonoacetic acid (PAA), we demonstrated that in HSV-1-infected THP-1 cells, activation of CXCL10, CXCL11, CCL13, CCL2, CCL4, CCL13 and CMKLR1 was significantly downregulated, suggesting that chemokine activation is partially 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. Importantly, when neuronal (SH-SY5Y) and epithelial (HEp-2) cells were exposed to supernatants derived from pistachio extracts and zeaxanthin-treated infected THP-1 cells, we observed a significant reduction in the production of new HSV-1 viral progeny compared to the untreated infected THP-1 cells. In conclusion, the 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 chemokine-mediated cell response, including CXCL10, CXCL11, CCL13, CCL2, and CCL4, and the receptor CMKLR1, to maintain a delicate balance with the host cell, thereby promoting viral persistence.