High prevalence and mortality rates of cervical cancer create an imperative need to clarify the uniqueness of HPV (Human Papillomavirus) infection, which serves as the key causative factor in cervical malignancies. Understanding the immunological details and the microenvironment of the infection can be a useful tool for the development of novel therapeutic interventions. Chronic infection and progression to carcinogenesis are sustained by immortalization potential of HPV, evasion techniques, and alterations in the microenvironment of the lesion. Inside the lesion, Toll-like receptors expression becomes irregular; Langerhans cells fail to present the antigens efficiently, tumor-associated macrophages aggregate resulting in an unsuccessful immune response by the host. HPV products also downregulate the expression of microenvironment components which are necessary for natural-killer cells response and antigen presentation to cytotoxic cells. Additionally HPV promotes T-helper cell 2 (Th2) and T-regulatory cell phenotypes and reduces Th1 phenotype, leading to suppression of cellular immunity and lesion progression to cancer. Humoral response after natural infection is inefficient, and neutralizing antibodies are not adequate in many women. Utilizing this knowledge, new endeavors, such as therapeutic vaccination, aim to stimulate cellular immune response against the virus and alter the milieu of the lesion. 1. Introduction All sexually active individuals are liable to HPV infection during sexual intercourse. It is assessed that the risk of sexually active women to be infected sometime in their life is nearly 80% [1]. HPV infection alone is not adequate for the advancement to cervical cancer and other risk conditions such as smoking, prolonged oral contraception consumption, coinfections, and multiparity, immune-related diseases appear to lead the infection on the route of carcinogenesis [2–5]. The vast majority (90%) of HPV infections are cleared by the patients’ immune system in three-year followup, whereas from the 10% that become chronic only 1% result in cervical cancer. The infection is usually clinically silent with absence of common genital symptoms, but it can be manifested with a spectrum of lesions from genital warts to invasive cancer [6]. Suppression of host immunity, persistence of the infection, and integration of the virus into the host DNA help a low grade squamous intraepithelial lesion (LSIL) to step up to high grade squamous intraepithelial lesion (HSIL) and even to invasive carcinoma of the cervix [7]. 2. Materials and Methods We
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