Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Short Communication Intervirology 2008;51:230–234 DOI: 10.1159/000156481 Co-Expression of HSV2 and Chlamydia trachomatis in HPV-Positive Cervical Cancer and Cervical Intraepithelial Neoplasia Lesions Is Associated with Aberrations in Key Intracellular Pathways Pierpaolo Paba a Daniela Bonifacio b Luigi Di Bonito b Domenico Ombres a Cartesio Favalli a Kari Syrjänen c Marco Ciotti a a Laboratory of Clinical Microbiology and Virology, University Hospital Tor Vergata, Rome, and b Department of Pathology, University of Trieste, Trieste, Italy; c Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland sions; p = 0.023, p = 0.045, and p = 0.020 as well as survivin, p = 0.026. Survivin was the only marker that was overex- pressed also in HSV2+/HPV+ lesions, p = 0.027. Conclusions: CT infection favors the entry and persistence of multiple HR-HPV types, which leads to viral integration, inhibition of apoptosis, overexpression of E6/E7 oncogenes and cell transformation. Copyright © 2008 S. Karger AG, Basel Cervical cancer (CC) is the third most frequent cancer in women [1] and infection with oncogenic human papil- lomavirus (HPV) types is the major risk factor for the development of invasive CC [2]. However, cofactors that act in conjunction with HPV could play an important role in cervical carcinogenesis. It has been suggested that Chlamydia trachomatis (CT) and herpes simplex virus type 2 (HSV2) infections could act as such potential co- factors in the development of CC [3, 4]. Indeed, there is evidence that some regions of the HSV2 genome, namely BamHI or Bgl II N fragments, have the potential to trans- form rodent or human cells in vitro [5], and these se- quences have been frequently found in CC cells associ- ated with HPV sequences [6] . Key Words Human papillomavirus  Herpes simplex virus type 2  Chlamydia trachomatis  Biomarkers  Multiple infections  Synergism  Cervical carcinoma  Cervical intraepithelial neoplasia Abstract Objective: Oncogenic human papillomaviruses (HPVs) are the etiological agents of cervical cancer. Different cofactors might be needed for malignant transformation, but they still remain elusive. Methods: To delineate the role of Chlamydia trachomatis (CT) and herpes simplex virus type 2 (HSV2) in HPV-positive cervical intraepithelial neoplasia (CIN) lesions and cervical carcinoma a series of 149 cervical cancer and CIN biopsies were analyzed for CT and HSV2 DNA by PCR, and HPV genotyped by InnoLipa. Monitoring of aberrations in key intracellular pathways due to CT/HSV2 and HPV co-ex- pression were analyzed with 13 biomarkers. Results: Of the 149 samples tested, 136 were HPV DNA positive; 32/136 con- tained also CT DNA and 29 HSV2 DNA. Detection of CT was significantly (p = 0.0001) related to multiple-type HPV infec- tions, while HSV2 was of borderline significance (p = 0.053). Of the 13 biomarkers tested, cytoplasmic and nuclear NF-B and VEGF-C were significantly increased in CT+/HPV+ le- Received: April 23, 2007 Accepted after revision: July 25, 2008 Published online: September 24, 2008 Dr. Marco Ciotti Laboratory of Clinical Microbiology and Virology, University Hospital Tor Vergata Viale Oxford, 81 IT–00133 Rome (Italy) Tel. +39 062 090 2087, Fax +39 062 090 2078, E-Mail marco.ciotti@ptvonline.it © 2008 S. Karger AG, Basel 0300–5526/08/0514–0230$24.50/0 Accessible online at: www.karger.com/int