Persistence of human papillomavirus infection: keys to malignant progression

Abstract

Human papillomaviruses (HPVs) are the etiologic agents of cervical and other epithelial cancers. Persistence of infections by high-risk HPV types is the single greatest risk factor for malignant progression. Although prophylactic vaccines have been developed targeting high risk HPV types, there is a continuing need to better understand the cell-host interactions that underlie persistent benign infection and progression to cancer. In this review, we summarize the molecular events that facilitate the differentiation-dependent HPV life cycle, how the life cycle is organized to facilitate viral persistence, and how the activities of HPV regulatory proteins result in malignancy. Human papillomavirus infection leading to cancerViruses cause approximately 15% of human cancers, and of these nearly half are attributable to human papillomaviruses (HPVs) 1 . Infections by HPVs in the genital tract are the most common sexually transmitted viral infection 2 . Although progression to cancer is a rare event, the high prevalence of HPV infection makes HPV-related cancers, including cervical and other anogenital cancers, among the most common malignancies. It is estimated that over 450,000 new cases of cervical cancer are diagnosed each year making this the second most prevalent cancer in women worldwide 1 . The effective utilization of the Papanicolaou (Pap) smear to recognize cellular abnormalities associated with HPV infection has resulted in a reduction in the number of cases of cervical cancer in the US by 80% in the last 50 years. Despite this decrease, approximately 11,000 women are diagnosed with cervical cancer annually in the US and approximately 3700 die of this disease 2 . In addition, highrisk HPV infection is responsible for approximately 3,000 cases of anal cancer and over 3500 cases of oropharyngeal cancer annually in the United States 2 .Papillomaviruses are small, non-enveloped DNA viruses that infect stratified squamous and cutaneous epithelia 3 . Over 120 different types of HPVs have been identified and approximately one-third of these types specifically target epithelial cells in the genital tract. The remaining types infect epithelial cells in other tissues including cutaneous epithelia. The HPV types that infect the genital mucosa can be divided into two groups. The high-risk (HR) types, including HPV16, 18, 31 and others, are frequently found in cervical cancers. By contrast, the low-risk (LR) types, including HPV6 and 11, also infect the genital epithelia, but are rarely detected in malignancies 4 . Two prophylactic vaccines (Gardasil (Merck) and Ceravrix (GSK)) against the HR types HPV16 and 18 were recently approved

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

“…Persistent infection with high‐risk HPV is the main aetiological factor in cervical carcinogenesis 2, 3, 4. However, HPV infection alone does not sufficiently explain the occurrence of cervical cancer because HPV oncogenes E6 and E7 can immortalize but do not transform human epithelial cells 5, 6. Thus, HPV infection can be considered an initial hit in the multistep carcinogenesis that leads to cervical cancer, and additional factors are involved in the progression of HPV‐infected lesions to cancer 7.…”

Human Papillomavirus: Biology and Pathogenesis

“…For a better understanding, the life cycle of HPV was divided into two parts: a maintenance phase and differentiation-dependent phase (Bodily & Laimins, 2011).…”

“…HPV genomes replicate in the nucleus of the basal cell layer, where the viral replication is considered nonproductive and the virus establishes itself as a low-copynumber episome by using the host DNA replication machinery (Moody & Laimins, 2010). In this way, viral proteins are expressed at very low levels in undifferentiated cells, and this contributes to immune avasion and persistence (Bodily & Laimins, 2011).…”

“…E6 and E7 can induce centrosomal abnormalities resulting in abnormal centrosome reduplication, leading to abnormal numbers of centrosomes Furthermore, abrogation of cell-cycle checkpoints through the targeting of p53 and pRB family members allows retention of cells with chromosomal abnormalities (Münger et al, 2004). This can result in genetic changes that accumulate over an extended period of time until resulting in a combination of genetic abnormalities, allowing cancer development (Bodily & Laimins, 2011).…”

AKNA as Genetic Risk Factor for Cervical Intraepithelial Neoplasia and Cervical Cancer

“…Persistence of infections by HR-HPV types is the single greatest risk factor for malignant progression. Although prophylactic vaccines have been developed that target HR-HPV types, there is a continuing need to better understand the virus-host interactions that underlie persistent benign infection and progression to cancer (Bodily & Laimins, 2011). Even though HPV is considered to be a necessary but not sufficient cause for CC, the hereditary component has been reported and several studies indicate that genetic background of the host is important for CC susceptibility and for the carcinogenic process.…”