Role of Herpes Simplex Virus Type-1 (HSV-1) in Modulating VEGF-A Expression Among Iraqi Patients Receiving Chemotherapy: A Cross-Sectional Molecular Study
DOI:
https://doi.org/10.63939/rnw1e064Keywords:
HSV-1, VEGF-A, chemotherapy, angiogenesis, qPCR, viral reactivationAbstract
Background: Herpes simplex virus 1 (HSV-1) establishes lifelong latency with periodic reactivation, and is of particular concern in immunocompromised patients, such as those receiving treatment with chemotherapy. Experimental data suggest that upon infection, HSV-1 induces the expression of vascular endothelial growth factor A (VEGF-A), a key mediator of angiogenesis and inflammation. However, the link between HSV-1 reactivation and physiological or systemic VEGF-A in patients receiving oncological therapy have not been examined broadly.
Methods: A cross-sectional molecular study to investigate the relationship between HSV-1 reactivation and VEGF-A expression in Iraqi chemotherapy patients.
Methods: 300 subjects (200 chemotherapeutic patients and 100 control not receiving chemotherapy) were recruited. HSV-1 status was assessed by serology (IgG, IgM) and qPCR detection of viral DNA in oral swabs and plasma. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum VEGF-A concentrations and reverse transcription qPCR was performed to quantify peripheral blood mononuclear cells levels of VEGFA mRNA. A multivariable linear regression was conducted to determine the independent relationship between positivity for HSV-1 DNA and log-transformed VEGF-A levels while controlling for demographic, clinical, and immunological variables.
Results: HSV-1 DNA was found in 18% of patients undergoing chemotherapy versus 5% of controls (p < 0.001). Serum VEGF-A levels in chemotherapy patients were
significantly higher than controls (median 412 according to 221 pg/mL; p < 0.001). In chemotherapy patients, individuals who were positive for HSV-1 DNA had significantly higher serum VEGF-A (median 712 with 368 pg/mL, p < 0.001) and increased expression of VEGFA mRNA (median fold change 3.94 compare with 1.63, p < 0.001). Oral viral load positively correlated with serum VEGF-A (Spearman ρ = 0.58, p < 0.001). In a multivariable analysis, positivity for HSV-1 DNA remained independently associated with higher log (VEGF-A) (β = 0.41, 95% CI 0.28–0.54, p < 0.001).
Conclusions: Reactivation of HSV-1 is independently correlated with enhanced VEGF-A expression in un-females and non-HSV infected chemotherapy doomed fatalities. This observation hinted that viral reactivation upon immune suppression might drive systemic angiogenic and inflammatory signaling. The clinical implications of HSV-1–mediated VEGF-A upregulation in oncology settings warrant examination in prospective studies. In the state of virus reactivation, qPCR was used to quantify HSV-1 and VEGF-A expression level.
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References
1. Looker KJ, Johnston C, Welton NJ, James C, Vickerman P, Turner KME, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One. 2015;10(10):e0140765.
2. Whitley RJ, Roizman B. Herpes simplex viruses. In: Fields Virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1823–97.
3. Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, et al. A systematic review of viral infections associated with oral involvement in cancer patients. Support Care Cancer. 2010;18(8):993–1006.
4. Chemaly RF, Torres HA, Hachem RY, Nogueras GM, Aguilera EA, Younes A, et al. Herpes simplex virus infections in patients with cancer. Clin Infect Dis. 2006;43(4):493–500.
5. Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, et al. MASCC/ISOO clinical practice guidelines for mucositis secondary to cancer therapy. Cancer. 2014;120(10):1453–61.
6. Baden LR, Swaminathan S, Angarone M, Blouin G, Camins BC, Casper C, et al. Prevention and treatment of cancer-related infections. J Clin Oncol. 2016;34(35):405–23.
7. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.
8. Pages G, Pouyssegur J. Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors. Cardiovasc Res. 2005;65(3):564–73.
9. Wuest T, Carr DJJ. VEGF-A expression by HSV-1–infected cells drives corneal lymphangiogenesis. J Exp Med. 2010;207(1):101–15.
10. Lee S, Zheng M, Kim B, Rouse BT. Role of VEGF in herpes simplex virus–induced angiogenesis. Invest Ophthalmol Vis Sci. 2012;53(8):4573–80.
11. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.
12. Dirix LY, Vermeulen PB, Pawinski A, Prové A, Benoy I, De Pooter C, et al. Elevated levels of circulating VEGF in cancer patients. Br J Cancer. 1997;76(2):238–43.
13. Chemaly RF, Torres HA, Hachem RY, Nogueras GM, Aguilera EA, Younes A, et al. Herpes simplex virus infections in patients with cancer. Clin Infect Dis. 2006;43(4):493–500.
14. Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, et al. A systematic review of viral infections associated with oral involvement in cancer patients. Support Care Cancer. 2010;18(8):993–1006.
15. Whitley RJ, Roizman B. Herpes simplex viruses. In: Fields Virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013.
16. Baden LR, Swaminathan S, Angarone M, Blouin G, Camins BC, Casper C, et al. Prevention and treatment of cancer-related infections. J Clin Oncol. 2016;34(35):405–23.
17. Wuest T, Carr DJJ. VEGF-A expression by HSV-1–infected cells drives corneal lymphangiogenesis. J Exp Med. 2010;207(1):101–15.
18. Pages G, Pouyssegur J. Transcriptional regulation of the vascular endothelial growth factor gene. Cardiovasc Res. 2005;65(3):564–73.
19. Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013;38(5):870–80.
20. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.
21. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.
22. Dirix LY, Vermeulen PB, Pawinski A, Prové A, Benoy I, De Pooter C, et al. Elevated levels of circulating VEGF in cancer patients. Br J Cancer. 1997;76(2):238–43.
23. Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, et al. MASCC/ISOO clinical practice guidelines for mucositis secondary to cancer therapy. Cancer. 2014;120(10):1453–61.
24. Looker KJ, Johnston C, Welton NJ, James C, Vickerman P, Turner KME, et al. Global and regional estimates of HSV-1 infections. PLoS One. 2015;10(10):e0140765
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