HPV Infections: Diagnosis, Prevention, and Treatment

Viruses are related to 15-20% of human cancers worldwide. Many studies focused on clarifying the molecular mechanisms and genetic alterations caused by oncogenic viruses. Among different oncoviruses, human papillomaviruses (HPVs) are small, non-enveloped, double-stranded DNA viruses, which can infect mucosal or cutaneous epithelia. Many HPVs have been classified as low-risk viruses associated with benign warts in the general population. Other HPVs entitled as the high-risk HPV types cause several important human cancers including cervical cancer, other anogenital cancers and head and neck tumors. A general description of HPV types and their association with different disorders are presented in this chapter.

Papillomaviruses (PVs) are small non-enveloped viruses with a circular DNA genome encoding the viral early and late genes. The expression of late gene generates the structural L1 and L2 proteins, whereas early gene expression produces the regulatory proteins (E1-E8). The L1 and L2 proteins have important roles in virion assembly. Among the regulatory proteins, E7 and E6 oncoproteins play an important role in benign and also malignant transformation. For instance, a variant of HPV16 with the minimal differences in E6 sequence (Q14H/H78Y/L83V) found in cervical cancers is more effective for virus replication and maintenance as well as cell immortalization compared to other HPV types. Regarding the role of early proteins in the HPV life cycle, all proteins encoded by the HPV genome and their functions will be described in this chapter.

During the last years, several researchers have properly focused on classifying variants of human papillomaviruses (HPVs). HPV variants are different in their biological, molecular and chemical properties. Thus, this genomic diversity can represent differences in the natural history and pathogenicity of HPVs. For instance, high-risk HPV variants such as HPVs 16 and 18 can confer various risks of viral persistence in the human cervix and cause cervical cancer. Moreover, low-risk HPV variants including HPVs 6 and 11 can play an important role in the development of anogenital and cutaneous warts, and recurrent respiratory papillomatosis (RRP). Herein, we will discuss main and novel types of HPVs and their correlation with intensity of diseases.

Genital HPV infections are the most common of all sexually transmissible agents. The HPV life cycle is dependent on host cell differentiation with late viral events such as structural gene expression and viral genome amplification in the upper layers of the stratified epithelium. Indeed, the virus destabilizes host chromatinremodeling factors to facilitate viral replication and transcription. Generally, the life cycle of the virus is divided into major steps including entry, establishment of the nonproductive infectious state, maintenance of the non-productive infectious state, and productive stage. In this chapter, we briefly explain transmission and the life cycle of HPVs in host cells.

Cervical infections caused by HPV appear at any age as a benign disorder unless they persist. Different studies on transmission of HPV showed that the rates of transmission between heterosexual couples widely vary dependent on some factors such as intervals between testing points, rates of concordance or discordance at baseline, and difficulty in defining established infections versus contamination. This chapter describes the natural history of (HPV) infection in different stages of cancers in women and men.

Human papillomavirus (HPV)-associated cancers include cervical cancer, vulvar cancer, penile cancer, vaginal and anal cancer and a subset of head and neck cancers. Thus, effective vaccination against HPV infection is recommended to decrease their incidence and progression in the world. The FDA of the USA has approved two preventive vaccines to inhibit the spread of HPV. However, preventive vaccines do not exert therapeutic effects on pre-existing HPV infections, so therapeutic vaccines are being developed to generate a cell-mediated immune response to infected cells. HPV vaccination might be useful not only for prevention of cervical cancer, but also for the reduction of other related cancers. Herein, HPV-related cancers will be explained to consider their preventive and therapeutic pathways in future.

Differences in prevalence rates of HPV infections are observed worldwide. Cervical cancer remains a major public health concern, especially in developing countries. Cancers of the anus, penis, vagina, and vulva are relatively uncommon cancers, but their incidence is gradually increasing in the world. Indeed, the epidemiology of HPV-associated anogenital cancers of the cervix, anus, penis, vagina and vulva is changing, likely due to increasing HPV transmission secondary to changes in sexual behaviour. Molecular epidemiologic studies indicate that certain HPV types were highly prevalent among women aged below 30 years with a peak in the 21-25 year age group and those who are above 30 years. Thus, screening programs and the HPV vaccines are required to prevent the anogenital cancers. In this chapter, the epidemiology of HPV-related cancer types will be studied based on new data.

The induction of immunotolerance of the host's immune system by the persistent infection of HPV is one of the most important mechanisms for cervical lesions. The immune system modifications induced by HPV infection include tumorassociated macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T-helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and down-regulated DC activation. In this chapter, the effects of HPV and its mechanism of action will be discussed on immune system.

Up to now, the major environmental risk factors have been reported to develop cervical cancer such as smoking, parity, nutrition, and HPV infections. However, it is not clear whether the association of these environmental factors with cervical cancer leads to further sensitivity against HPV infection (i.e., as cofactors to HPV infection) or they may act as independent risk factors in cervical carcinogenesis. In this chapter, the correlation of HPV infections and risk factors with various cancers will be described.

Human papillomaviruses are associated with various cutaneous or mucosal benign and malignant neoplasms. The majority of available data on routine HPV diagnostics has been focused on evaluating the cervix. There is limited data on the efficiency of HPV diagnostics in cutaneous lesions. The balance between analytical and clinical sensitivity is critical for the specificity of a routine HPV test. Furthermore, HPV16 and HPV18 confer a higher risk for the development of a cervical intraepithelial lesion 2+ compared to the other HPV high-risk types. Thus, it is suitable to detect these HPV types individually. Up till now, HPV diagnosis has been mainly based on DNA detection using available amplification methods. PCR techniques could be used as type-specific or consensus PCRs. Among the methods, the Hybrid Capture 2 test has become the gold standard in routine HPV testing due to its high clinical sensitivity and its relatively high specificity. Briefly, three tests have received FDA approval including CervistaTM, signal amplification; CobasTM HPV test, real-time PCR; APTIMATM HPV, RNA test. On the other hand, the broad cytology-based screening programs have reduced the incidence of cervical cancer by 70% in the developed world. However, more than 270,000 annual cervical cancer-related deaths occur in developing countries due to their inability to improve a high-quality cytologybased screening program. In this chapter, different diagnosis and screening methods of HPV infections are evaluated in women worldwide.

HPV infection as the etiologic agent of cervical cancer and also other epithelial cancers, has led to the development of three FDA-approved prophylactic HPV vaccines composed of virus-like particles (VLPs). Development of prophylactic HPV vaccines could decrease HPV-associated diseases especially HPV-16 and -18 in the world. Recently, in order to enhance protection against other HPV genotypes, second-generation vaccines are underway. For example, A novel safe HPV L1-based nonavalent vaccine was designed to prevent precancerous lesions related to high-risk HPV types 16/18/31/33/45/52/58, as well as anogenital warts associated with HPV types 6/11. This vaccine is in the advanced stage of phase III clinical trials. Other second-generation vaccines were based on L1-pentameric subunits and also the minor capsid protein L2 that have shown to be effective in preclinical studies. In this chapter, some major methods about the prevention of HPV-associated diseases will be discussed.

In spite of the use of prophylactic vaccines to prevent some HPV infections, HPV-associated diseases have remained as a significant public health problem for decades especially in the developing world. There is an urgent need for the treatment of existing HPV-related lesions. The current treatment of neoplastic HPV-associated conditions includes HPV vaccines, targeted therapy of cervical cancer, drug therapy, and stem cell therapy. Herein, some recent findings on therapy of HPV-induced intraepithelial neoplasias will be summarized.

Human papillomaviruses (HPV) infection can cause cervical, vaginal and vulvar cancers in women and penile cancer in men. HPV can also cause oropharyngeal and anal cancers and genital warts in both women and men. HPV types 16 and 18 are the most carcinogenic types and are responsible for about 70% of the cervical cancers. HPV types 31, 33, 35, 45, 52 and 58 account for an additional 20% of the cervical malignancies worldwide. Currently, three vaccines are available on the market that prevent HPV infection including bivalent Cervarix targeting HPV types 16 and 18, quadrivalent Gardasil targeting HPV 16, 18, 6 and 11, and 9-valent Gardasil-9 targeting HPV 31, 33, 45, 52 and 58 in addition to HPV 16, 18, 6 and 11. The present chapter discusses the HPV vaccines and their immunogenicity, efficacy, safety and side effects.

Up to now, a large number of HPV therapeutic vaccines have been developed targeting E6 and E7 oncoproteins including peptide/protein-based vaccines, live vector vaccines, cell-based vaccines and nucleic acid-based vaccines; each with advantages and disadvantages. These vaccines control HPV infection through cellmediated immunity in preclinical and clinical trials, e.g., adoptive T-cell therapy in patients with advanced cervical cancer and/or DNA-based vaccine in HPV-16 or HPV- 18 positive CIN clinical trials. In this chapter, the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical diseases will be explained, focusing on vaccines that have been tested in clinical trials.

Persistent infection with human papillomavirus (HPV) is a key factor in the development of precancerous lesions and invasive cervical cancer. Prophylactic vaccines are an effective approach to reduce HPV-related disease burden. Regarding the studies, at least 110-120 countries have implemented Cervarix™ and Gardasil™ for induction of protective effects against HPV infections. On the other hand, several clinical trials are underway for therapeutic HPV vaccination. Special approaches is considered to increase the potency of therapeutic vaccines including the use of effective adjuvant, selection of strong immunogen and combination therapies to overcome tumor immune suppression. In this chapter, we will summarize main preventive and therapeutic HPV vaccines in preclinical and clinical trials.

The Human Papillomavirus (HPV) vaccines have been widely introduced in the national immunization programs of the medium and high income countries. Both bivalent and quadrivalent vaccines are generally known as safe and well-tolerated. Site injection symptoms are the most frequent adverse events reported. Among them, pain was generally the most frequently referred local symptom. It was shown that the occurrence of serious adverse events was similar in both vaccine and control groups. Regarding to the reports, no deaths from the introduction of the two vaccines have been attributed to HPV vaccination. Studies on the safety of the vaccine in some populations (men, women older than 25 years, HIV+ girls) have given satisfactory results. However, there are some unresolved issues in the current HPV vaccines for different populations such as safety and duration of protection, cross-protection, tolerability, and side effects (e.g., pain, swelling and redness, autoimmune and neurological conditions) similar to other vaccines. Briefly, we explain the possible adverse effects of common HPV vaccines in this chapter.

All countries are encouraged to introduce routine HPV vaccination into their health programs. A range of screening and treatment protocols prevent cervical cancer in women already infected with HPV. The clinical trials indicated that HPV-based screening in women above the age of 30 is the most effective option. The main problems are that the licensed HPV vaccines are too expensive for universal use and they are not targeted against all HPV genotypes. Thus, the future generation of preventive vaccines must address two main issues such as lowering the cost of the vaccine for developing countries, and increasing the number of HPV types covered in order to maximize protection against HPV-associated malignancies. Moreover, several factors demonstrate the need for a therapeutic vaccine rather than preventive vaccine. The most critical of these factors is the high prevalence of existing HPV infection worldwide. In this chapter, future prospects of preventive and therapeutic vaccines will be discussed. Among these methods, combined therapy is of interest for improvement of these vaccines.