A wide range of diseases have papillomaviruses (PVs) as their causative agent and human papillomaviruses (HPVs) are behind a great portion of anogenital and some non-genital malignancies worldwide. In Pakistan fewer reports are based on occasional testing from the different regions of the country. Present study investigated incidence and etiological involvement of HPV in cervical cancer in Pakistan. Moreover, prevalence of HPV in other anogenital and non-genital cancers such as breast and lung cancer was also observed in the study subjects. This study also aimed at exploring the functional aspect of HPV E5 oncoprotein. HPV E5 has been documented as a significant player in the productive stage of the viral life cycle and is seen to exert its effect through enhancing the epidermal growth factor receptor (EGFR) pathway. In epithelial malignancies such as HPV-positive cervical cancer, EGFR is among the most frequently activated proto oncogenes. Negative regulator of EGFR family include LRIG1 (leucine-rich repeats and immunoglobulin-like domains protein 1) which has been recently discovered. Though E5 role in enhancing EGFR signaling is largely documented but all aspects of the receptor signaling have not been taken under consideration such as the possible interplay between E5 and LRIG1 during EGFR signaling. In order to address the possible interplay between viral factor E5 and host factor LRIG1 that may lead to the development of HPV related disease, first role of LRIG1 in cervical cancer cell lines was studied in relation to EGFR. Further, human foreskin keratinocytes (HFKs) expressing a functional E5 and E5 knockout counterparts were utilized to observe the effect of E5 on LRIG1 and its activity. Following differentiation, HPV18 HFKs began expressing functional E5 in semisolid medium, and a reduction in LRIG1 protein expression was seen as compared to the ABSTRACT xx knockouts suggesting the possible role of E5 in downregulating EGFR negative regulation pathway. Messenger RNA and protein expression analysis confirmed the decrease in LRIG1 expression in accordance with the expression of E5 as well as impact of E5 in delaying differentiation and downregulating LRIG1 at varying levels of differentiation in keratinocytes. It can be speculated that hijacking control from LRIG1, E5 provides that ‘added value’ to the HPV types expressing it. However through co-immuno-precipitation experiment no physical binding between the two proteins which could be responsible for this effect was observed. Thus it may be concluded that E5 way of affecting LRIG1 may not be direct but is potent enough to render the protein incapable of performing its function. Moreover it was seen that by physically blocking tyrosine kinase domain of EGFR, LRIG1 levels were successfully restored in E5 expressing keratinocytes. It also suggests that, if utilized, LRIG1 may act synergistically with tyrosine kinase inhibitors in downregulating EGFR pathway in an HPV infection. In conclusion present study helped us to explore the unaddressed role of HPV E5 in influencing negative regulation of EGFR pathway. Thus, the study provided basis for future studies which may target E5 as an important oncoprotein of HPV and LRIG1 as a tumor suppressor for therapeutic purpose.