083 | HSV-1 replication and chemokines activation in human monocytes are suppressed by Pistacia vera l. extracts

Rosamaria Pennisi¹, Marianna Costa^1|2, Paola Trischitta^1|2, Giuseppina Mandalari¹, Maria Teresa Sciortino¹. | ¹Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy; ²Department of Chemistry, Biology and Biotechnology, University of Perugia, Italy.

Herpes simplex virus type 1 (HSV-1) infection represents a significant clinical challenge, with a growing need for alternative therapeutic strategies that reduce side effects, overcome drug resistance phenomena, and control the intense inflammatory response induced by the virus. Pistachios (Pistacia vera L.) are known to contain polyphenols, pharmacologically active compounds with both immunomodulatory and antiviral activities [1,2]. This study demonstrates, for the first time, that natural pistachio extracts exert potent antiviral and immunomodulatory effects against HSV-1 in human monocytic THP-1 cells, a crucial cellular model for understanding the innate immune response. Using a multilevel experimental approach integrating transcriptional analysis via RT2 Profiler PCR array, viral replication assays, and western blot analysis, we identified a complex mechanism of action through which natural raw (NRRE) and roasted (RURE) pistachio extracts interfere with multiple stages of the HSV-1 replication cycle. Results reveal that treatment with NRRE and RURE significantly reduces viral replication, as evidenced by reduced viral DNA levels, marked suppression of key viral transcripts (ICP0, UL42, US11), and viral protein ICP8. The most significant impact concerns the discovery that HSV-1 induces massive chemokine activation in monocytes, upregulating 34 genes out of 84 analyzed, and that this inflammatory response is significantly attenuated by pretreatment with pistachio extracts. Specifically, CXCL10, CXCL11, CCL2, CCL4, CCL13, and the receptor CMKLR1, which are strongly expressed during HSV-1 replication, are drastically downregulated at both the transcriptional and protein levels by treatment. Zeaxanthin, a bioactive carotenoid in pistachio extracts, reproduces the antiviral and anti-inflammatory effects. Experiments with phosphonoacetic acid and THP-1-dnIκBα cells revealed that chemokine induction depends on active viral replication and NF-κB activation. Notably, conditioned supernatants from infected monocytes treated with pistachio extracts or zeaxanthin significantly reduce viral progeny production in permissive neuronal (SH-SY5Y) and epithelial (HEp-2) cells. In conclusion, Pistacia vera L. extracts and zeaxanthin appear to be promising therapeutic candidates for controlling both HSV-1 replication and inflammatory complications. This is especially relevant in immunoprivileged tissues such as the brain, eyes, and genital tract, where inflammation plays a significant role in pathology. This study offers valuable insights into virus-host interactions, showing how HSV-1 modulates cellular responses through specific chemokines (CXCL10, CXCL11, CCL2, CCL4, CCL13) and the receptor CMKLR1 to maintain a balance that favors viral persistence, opening new avenues for targeted therapeutic interventions.