title: Development of biomarker panel to predict, prevent and create treatments tailored to the persons with human papillomavirus-induced cervical precancerous lesions.
abstract: BACKGROUND
  Human papillomavirus (HPV) induce many cancer conditions and cause cervical cancer, second in frequency of malignant disease in women.The aim was to develop biomarker panel for HPV-induced cervical precancerous diseases in patients infected with herpes simplex virus (HSV).
  
  
  METHODS
  The study involved 71 women with cervical precancerous diseases (mean age 26 ± 5 years) revealed by colposcopic, cytomorphological, and ultrasound signs which were assessed according to the following: first group, 44 patients infected with HPV; second group, 27 HPV-negative patients; and third group, 30 healthy patients (controls). In cervical specimen, we identified HPV DNA of different oncogenic risk types by polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) kits (JSC SPC 'DiaprofMed') were used for detecting antibodies to HSV1 and/or HSV2 and for determining the avidity index. The production of pro-inflammatory cytokines, interferon-γ (IFN-γ), IFN-α, TNF-α, and interleukin-1β (IL-1β), and anti-inflammatory cytokines, IL-4, IL-10, and transforming growth factor-β1 (TGF-β1), were studied by ELISA.
  
  
  RESULTS
  In HPV-induced cervix precancerous diseases, we identified low-avidity IgG antibodies to HSV serum of 20 patients; in the serum of 17 patients, we identified average-avidity antibodies, and high-avidity antibodies were found in 2 patients only. In 14 HPV-negative patients, we found low-avidity IgG antibodies to HSV; in 10 patients, medium avidity. Patients with low-avidity IgG antibodies to herpes virus showed high and medium oncogenic risk HPV types and a decrease of IFN-γ compared to patients with medium-avidity IgG antibodies. Production of IFN-γ was suppressed also in HPV-negative patients with cervical precancers, but we found low- and medium-avidity IgG antibodies to herpes virus. In patients with low-avidity antibodies, we observed increased level of IL-10. Level of IFN-α, IL-1β, IL-2, and IL-4 did not change in patients of all groups, but TGF-β1 increased.
  
  
  CONCLUSIONS
  In HPV-positive patients, those with low-avidity IgG antibodies to HSV had immunosuppression, confirmed by increased TGF-β1 and violation of IFN-γ production. Therefore, in pro- and anti-inflammatory cytokines and IgG antibodies to HSV, their avidity is an important diagnostic biomarker of HPV-induced precancerous cervical diseases. Low-avidity IgG antibodies may be an indication for treatment with immunomodulators and antiviral drugs.
authors.forename: Liudmyla M
authors.initials: LM
authors.lastname: Lazarenko
authors.forename: Olena E
authors.initials: OE
authors.lastname: Nikitina
authors.forename: Evgen V
authors.initials: EV
authors.lastname: Nikitin
authors.forename: Olga M
authors.initials: OM
authors.lastname: Demchenko
authors.forename: Galyna V
authors.initials: GV
authors.lastname: Kovtonyuk
authors.forename: Larysa O
authors.initials: LO
authors.lastname: Ganova
authors.affiliation: Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, Zabolotny str, 154, Kyiv 03680, Ukraine. rostbubnov@gmail.com.
authors.forename: Rostyslav V
authors.initials: RV
authors.lastname: Bubnov
authors.forename: Veronika O
authors.initials: VO
authors.lastname: Shevchuk
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Nastradina
authors.forename: Viktoria V
authors.initials: VV
authors.lastname: Bila
authors.forename: Mykola Ya
authors.initials: MY
authors.lastname: Spivak