Immunopathology, Diagnosis and Treatment of HPV induced Malignancies

By Ashish Jain

Immunopathology, Diagnosis and Treatment of HPV induced Malignancies focuses on the human papilloma virus infection and associated cancers. In ten chapters, the book explains the deep knowledge about molecular mechanism in HPV pathogenesis and recent advanced tools applied in the field of HPV induced cancer and cures. In a nutshell, the book gives new insights and the associated challenges involved in the identification of promising drug and vaccine targets, current diagnostic tools, and advancements in current therapies against HPV induced cancers and other malignancies.

• Highlights the concept of Human papilloma virus infection, its pathogenesis, mechanisms involved in host immune response, clinical manifestations, prophylactic and therapeutic strategies, and recent advancements for the cure of HPV induced cancer
• Delineates new insights and challenges involved in the identification of promising drug and vaccine targets, current diagnostic tools, and advancements in current therapies against HPV induced cancer
• Provides comprehensive and conceptual knowledge that could be a milestone not only in the field of infectious cancers but also for researchers and scientists working on infectious cancer

• Language: English
• Publisher: Academic Press
• Release date: Aug 2, 2022
• ISBN: 9780323986441

Book preview

Preface

This book is meant to offer a complete overview of human papillomavirus (HPV) from discovery to the present day and its association with cervical malignancies. HPV is a group of more than 200 types of viruses and the most common viral infection of the reproductive tract. HPV is associated with cancers of the cervix, vulva, vagina, anus, penis, and oral cavity. Persistent infection of high-risk HPV (HR-HPV) can cause cervical cancer, the fourth most common cancer among women, with annually 570,000 new cases and 311,000 deaths reported globally predominantly in low- and middle-income nations. The book starts with an overview of HPV and provides a comprehensive update covering its pathogenesis, clinical manifestation, and current diagnostic tools. Further, it focuses on HPV-associated malignancies, host immune response against infection, animal models used in HPV research, and role of cervicovaginal microbiota and other sexually transmitted infections in disease progression and prevention. The book also elaborates available immunotherapies, novel targets on virus for drug development, different strategies for vaccine development, and future direction in HPV-induced cancer research. It is a useful reference for researchers, scientists, oncologists, academicians, undergraduate and postgraduate students and for anyone working in the HPV field to gain an understanding of different aspects of HPV-induced malignancies.

Chapter 1: An overview of HPV: Causes, symptoms, and clinical manifestations

Anuj Tripathia; Utkarsha Sahub    a Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN, United States

b Department of Microbiology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

Abstract

Human papillomavirus (HPV) is a common, dermatologic infection transmitted by skin contact and can cause a variety of anogenital diseases, including warts and lesions. In some cases, these warts and lesions will develop into cancers. HPV is a group of papillomaviruses that are highly species-specific and infect many vertebrate species. All the papillomaviruses are approximately similar in genome organization and physical structure and have 8 kb double-stranded, circular DNA viral genome with about 55-nm-diameter capsid. In most cases, HPV infection clears spontaneously, but due to the lack of an effective immune response, HPV infection can develop genital tract cancer or mouth cancer and neck cancer. There is no proper cure and treatment for all types of HPV cancers, but HPV vaccines are available to prevent infection by the most common HPV viruses. This chapter provides an overview of the epidemiology of human papillomavirus (HPV) infection, with its causes, symptoms, and clinical manifestations.

Keywords

Human papillomavirus; Structure of virus; Diagnosis; Malignancies; Treatment

1: Introduction

Papillomaviruses are a common group of viruses, including small, nonenveloped viruses that infect and induce cellular proliferation in cutaneous and mucosal epithelia of higher vertebrates [1,2]. Globally, about 570,000 cases per year in women and 60,000 cases in men are attributed to the human papillomavirus (HPV). Worldwide, 40% of all types of cancers, including approximately 2% from developed countries and 8% from developing countries, are caused by HPV infection. World Health Organization (WHO) report indicated that HPV causes 610,000 cancer cases and 250,000 deaths every year [3–6]. Papillomaviruses are highly species-specific and infect many vertebrates. All the papillomaviruses are approximately similar in genome organization and physical structure. The virus genome is composed of approximately 8 kb, double-stranded, circular DNA genome enclosed within a 55-nm-diameter capsid [1,7]. Based on their association with infection, cancer, and precursor lesions, HPVs can also be classified into two groups: high-risk (HR-HPV) and low-risk (LR-HPV) oncogenic types. In LR-HPV types, such as HPV6 and HPV11, infection can develop common genital warts or benign lesions, while in HR-HPV types, like HPV16 and HPV18, infection is associated with cervical cancer (CC) [8–11]. HR-HPV types are the causes of 40% of oral cancers and can induce anal, penile, vulvar, mouth, and throat carcinomas [12].

HPVs include over 100 different genotypes that infect basal epithelial cells of the skin or inner lining tissues. Some of the HPVs are responsible for cutaneous warts, while one subset of HPVs is found in the skin lesions associated with cutaneous squamous cell carcinomas [13,14]. Some HPVs are associated with infections that can cause benign, premalignant, and malignant lesions not only of the genital tract and anus but also of the oropharynx [14,15]. Out of 100 types of HPV, approximately 14 are cancer-causing in humans [8,16,17]. HPV infection is usually a transient dermatologic infection. Genital HPV infection is transmitted through sexual contact very shortly and is one of the most common sexually transmitted infections (STIs) in both men and women [18,19]. The HPV structural and nonstructural proteins play a crucial role in the attachment, entry, and replication of HPV. In addition, these proteins also help to avoid recognition by the host immune system [20]. During the initial phase of HPV infection, the virus maintains a low copy number to avoid immune recognition. Later, the rate of replication increases as the viral proteins hijack the cell cycle regulatory proteins and downregulated host immune factors [21]. The viral infection triggers a dysregulated inflammatory response that leads to viral persistence and tumor progression [22,23].

Once the HPV infection is established, it leads to different clinical manifestations such as warts, cervical dysplasia, or cervical intraepithelial neoplasia grade 1 (CIN 1). Generally, these lesions are self-limited by the host immune system within a year [24,25]. The precise immune mechanism involved in the clearance of HPV infection is still not fully explored. However, the major immune factors activated during HPV infection include tumor necrosis factor (TNF), interferon (IFN), transforming growth factor-β (TGF-β), Langerhans cells, and dendritic cells [25]. The role of TGF-β and TNF is not clear. They are reported to play both pro- and antiviral roles depending upon the experimental conditions [26–31]. Some of the HPV-induced clinical manifestations are not cleared by the host immune response, and their persistence can lead to malignant progressions such as squamous cell carcinoma and cervical adenocarcinoma [32]. Although it was initially reported that HPV primarily targets the women’s genital tract, it has also been associated with malignancies such as penile cancer, mouth cancer, and throat cancer [33–39].

Even after the past 50 years of HPV research, we still lack a complete understanding of HPVs and associated pathogenesis patterns. Also, most of the work on HPV biology is associated with HR-HPV strains. Our understanding of LR-HPV strains remains elusive. The early diagnosis of HPV can help in limiting the infection and prevent the associated clinical manifestations. Different diagnostic techniques used against HPV include Pap smear, nucleic acid detection, and colposcopy. Once the HPV is detected, the general treatment against the associated warts or lesions is administered. This includes different physical and chemical treatments [40–44]. The vaccines against HPV are mostly prophylactic and lack therapeutic applications. The development of therapeutic vaccines is a need in the present scenario. In this chapter, we have discussed an overview of the causes, symptoms, and clinical manifestations of HPV infection, and a better knowledge of different factors associated with HPV infection would pave the way for the development of effective prophylactic and therapeutic measures against HPVs.

2: Structure and biology of HPV

HPV infects cutaneous and mucosal epithelial cells in humans. The 8 kb viral genome encodes eight open reading frames (ORFs) [45]. The structure and function of the HPV genome are conserved and have three major regions:

(i)Long control upstream regulatory region (URR), located between the L1 and E6 open reading frames (ORFs). These regions have a promoter and regulatory elements that are involved in viral DNA replication and transcription.

(ii)Early regions encode the E1, E2, E4, E5, E6, and E7 proteins. These proteins are involved in viral gene replication, expression, and survival.

(iii)The late region encodes the structural proteins (L1 and L2).

This organization is shared among all α-HPVs. Certain HPV subtypes may lack some ORF because only four ORFs (those of E1, E2, L1, and L2) are necessary to ensure viral replication and infection [46]. All papillomaviruses possess a nonenveloped icosahedral capsid. The virus contains 360 molecules of L1 protein that forms 72 capsomeres [47–50]. HPV infection occurs at the basal layer of stratified squamous epithelial cells. Infection stimulates cell proliferation in the epithelium, and the cells undergo different changes from benign hyperplasia to dysplasia to invasive and later to carcinoma. In general cases, HPV infection is cleared by the host immune response, but some strains of HPV may develop carcinogenic warts and lesions [20] (Fig. 1).

Fig. 1

Fig. 1 Schematic representation of HPV pathogenesis.

The replication cycle of HPV can be divided into three different stages, namely establishment, maintenance, and amplification [51]. The viruses enter the host epithelium through microlesions and infect the basal epithelial cells [52]. The virus interacts with the host extracellular matrix via the capsid proteins [53,54]. This interaction results in the internalization of the virus particle inside the cell. Inside the target cell, the viral DNA is uncoated and transported to the nucleus, where it creates multiple copies [52]. E1 and E2 proteins are expressed in the HPV-infected basal layer of epithelium and regulate early viral DNA transcription. Approximately 50–100 HPV DNA copies per cell are stably maintained by E1 and E2 viral proteins in the undifferentiated basal cell [20,51]. In later stages, the E6 and E7 proteins are expressed and nullify the cell cycle regulation leading to continuous cell proliferation. HR E6 binds to the p53 tumor suppressor protein and leads to the rapid turnover of p53 [55,56]. E7 binds to the tumor suppressor retinoblastoma (Rb) family proteins and other proteins involved in cell cycle regulation [57,58]. Altogether, these events result in failure of cell cycle regulation and malignant transformation of infected host epithelial cells. Viral genomes are divided into HPV-infected basal cells. Infected basal cell leaves the basal layer and undergoes differentiation, due to action of the E7 protein [59]. Infected cells reenter in the S phase and convert into highly differentiated cells that have activated cellular replication factors required for viral replication. The E4 and E5 proteins are involved in the regulation of late viral functions [60]. The L1 and L2 proteins are assembled and form icosahedral capsids in later stages. L1 protein is the major capsid protein and is highly immunogenic, which is expressed in the last to avoid immune surveillance [61]. The mature viruses are assembled and released from the uppermost layers of the epithelium [61].

3: Causes of HPV infection

HPV infection is contagious; i.e., they are transmitted from one infected person to another via skin-to-skin contact [62]. The virus usually enters the human body, through a small cut, tear, or abrasion in the skin [15,19,63]. People get genital HPV infections through direct sexual intercourse, including vaginal, anal, and oral sex, and other skin-to-skin contacts in the genital region. Baby can get HPV infection through genital warts from HPV-infected mother [64].

4: HPV symptoms

HPV symptoms may be seen years after the initial infection. Early HPV infection does not cause any noticeable symptoms or health problems. The symptomatic HPV infections are marked by the presence of warts. Warts are very contagious and can spread through direct contact with a wart or indirectly when someone touches things that already have contact with a wart [63]. Some types of viruses cause warts to form, and in 90% of cases, they go away within two years. However, prolonged infection with HPV in the skin can cause serious health problems, including genital warts and throat warts. These types of warts can increase the risk of cancer in the body at later stages [16,65]. HPV warts can be categorized into two types, namely common warts and genital warts.

4.1: Common warts

HPV infection generally causes common warts, also known as flat warts or plantar warts. Common warts are bumpy, rough, sometimes hard, flat-topped, and slightly raised that tend to be formed on the hands, feet, fingers, and face or neck [14,18,66].

4.2: Genital warts

HPV infection with genital organs causes genital warts. They can be one small skin bump or cluster of bumps. These warts can cause burning, itching, and other symptoms. Genital warts can range in size and appearance, and they may be large or small; flat or cauliflower-shaped; white, pinkish-red, or purplish-brown colored. They can be formed on the vulva, cervix, penis, and anus [2,67]. The asymptomatic patients are silent carriers of infection. Asymptomatic shedding of HPV/DNA from the peri-anal region is very common. Especially, the transmission rate in patients with acute immunodeficiency syndrome (AIDS) can be up to 78.9% [62].

5: HPV diagnosis

Accurate diagnostics of infection at the right time is a golden chance to cure the disease and save the life. In recent eras, advanced diagnostic techniques have been available to identify and cure many infectious diseases [68]. Regular screenings with a physical examination of any warts or lesions can help diagnose HPV-related health problems earlier. Most warts are benign, but any of them can be converted into malignancies. Warts can occur on the skin, vagina, cervix, anus, and oropharyngeal areas [16,69]. The conventional methods for HPV diagnosis were less efficient and, thus, not suitable for proper HPV detection. These methods included cell culture electron microscopy and immunological methods [62]. Currently, more effective diagnostic techniques such as colposcopy and acetic acid test, biopsy, nucleic acid detection using PCR, in situ hybridization, Southern blot hybridization, and pap smear [62] are employed for HPV detection. Serological tests are not very promising for HPV infection due to weak host serological response. US preventive services task force (USPSTF) suggested that women aged between 21 and 29 should have a Pap test every three years [70]. Women aged between 30 and 65 should have a Pap test every three years with HPV test every five years. Abnormal Pap test in less than 30 years of age also should be confirmed through HPV test with the recommendation of doctor or gynecologist [65,70].

5.1: HPV tests in women

Regular Pap tests help to identify abnormal cells in women. According to guidelines of United States, at least 14 strains of HPVs are directly related to cancer, and confirmation of these strains should monitor cervical changes in patients [70–72]. Another technique includes the colposcopy of patients. Colposcopy allows biopsy targeted to the atypical areas. The biopsy of atypical areas is a crucial part of colposcopy since the treatment depends on the severity displayed by the biopsy sample. If the results suggest precancer (dysplasia) or malignancy, then treatment is a must. The dysplasia might be minor, temperate, or severe [62]. In addition, nucleic acid tests are also performed to diagnose the presence of HPV. These include polymerase gene reaction (PCR) and in situ hybridization [62].

5.2: HPV tests in men

Currently, there is no approved test for HPV diagnosis in men. The HPV nucleic acid test is only available for diagnosing HPV in women. Routine screening to check for HPV-related disease in men is not currently recommended by CDC [73,74]. Few doctors might perform an anal Pap test for men with an augmented risk of developing anal cancer. This includes men with HIV and men involved in anal sex with men [73,75].

6: Clinical manifestation of HPV infections

Globally, 20%–25% of all cancer cases are related to any infectious agents, and the virus alone is responsible for 12% of all human cancers [76,77]. HPV has a direct relation with approximately 30% of all infectious agent-related cancers [21]. In these cases, most deaths came from low- and middle-income countries. Now, HPV infection is gripping developed countries, and about 6.2 million people in the United States are annually infected with HPV [3,78]. The clinical manifestations of HPV during the initial phase are warts, CIN, lesions, etc. However, if left untreated, they may lead to CC, vaginal cancer, vulva cancer, anal cancer, penile cancer, and oropharyngeal cancer. Every year, HPV infection has arrested large number of populations in India [33]. The HPV-related cancer distribution in the Indian population is shown in Fig. 2.

Fig. 2

Fig. 2 HPV-related cancer distribution in the Indian population. [Different types of HPV cancer distribution in Indian male and female population]. (Data from HPV Information Centre reports, HPV CC in female prominent in Indian population).

Warts and lesions are generally cleared with effective treatment. However, their malignant progression may lead to different types of malignancies such as CC, vaginal cancer, penile cancer, vulvar cancer, mouth cancer, and throat cancer (Fig. 3).

Fig. 3

Fig. 3 Different malignancies caused by HPV in