Fig. (4) An imbalance in the interaction between viral and host factors may lead to clearance of infection and regression of lesions caused by HR-HPV or rather to progression to invasive cancer. Most CIN I and CIN II lesions (left side) regress spontaneously. The viral genome remains episomal in the infected keratinocytes and viral load is low as is the expression of viral proteins. Under these conditions, the cells can differentiate, which allows expression of capsid proteins and virus assembly and release. Antigen processing and MHC class I expression remain unaltered. Released viral particles are endocytosed, processed and presented by LCs triggering strong T cell responses. NK cells become activated through the NKG2D receptor upon binding to MICA/B expressed on the surface of the infected keratinocytes. In contrast, the vast majority of CIN III lesions progress to cancer as result of persistence of viral infection, which leads to integration of the viral DNA into the host genome and enhanced viral gene expression. The E6 and E7 viral products interfere with keratinocyte differentiation, and antigen presentation. MICA/B molecules undergo shedding by proteases released by the transformed cells and the soluble MICA/B-derived polypeptides cause a reduction in the number of NKG2D⁺ NK and T cells. Some risk factors such as sexual promiscuity, steroid hormones (contraceptives) and smoking may cooperate with the virus by increasing the viral load, enhancing gene expression and the rate of mutagenesis, respectively.