Knowledge on Human Papillomavirus Infections,Cancer Biology,Immune Interactions,Vaccination Coverage and Common Treatments: A Comprehensive Review

Introduction

HPV Genome

Papillomaviruses (PVs) are a type of DNA viruses characterized by a circular, double-stranded structure (Mirabello et al., 2018). Studies suggest that PVs have undergone coevolution with both animal and human host populations over the course of millions of years, and they are found worldwide, exhibiting a ubiquitous presence (Mirabello et al., 2018). The genetic material of the HPV is present in the form of an episome, consisting of around 8 kilobase pairs. This structure is divided into three distinct regions: two coding sections, which carry the instructions for producing viral proteins, and a noncoding region, responsible for regulating viral transcription and replication (Della Fera et al., 2021; Magalhães et al., 2021). Within the viral genome of HPV, the coding regions feature seven to nine open reading frames (ORFs) arranged into early and late regions. These ORFs are responsible for encoding two sets of highly conserved core proteins, E1 and E2, crucial for viral DNA replication, and L1 and L2, the structural proteins essential for capsid formation and vital in the assembly of virions (Della Fera et al., 2021; Magalhães et al., 2021). Beyond the core proteins, the HPV genome encompasses accessory genes such as E4, E5, E6, and E7. These accessory genes play a crucial role in modifying the host epithelium to establish a conducive environment for viral replication and aid in evading innate immune responses (Della Fera et al., 2021; Magalhães et al., 2021). The E1 and E2 proteins of HPV are primarily engaged in viral replication and the regulation of viral transcription. In contrast, the main oncogenes, E6 and E7, are thought to be instrumental in niche adaptation to specific anatomical or cellular regions, viral amplification, and unintentional stimulation of carcinogenesis (Mirabello et al., 2018). The noncoding section of the viral genome, also referred to as the upstream regulatory region, is situated ahead of the early region. It encompasses numerous cis-regulatory elements essential for transcriptional control, along with the origin of replication (Della Fera et al., 2021).

To date, researchers have identified a total of over 200 HPVs, which have been classified into five distinct categories: alpha, beta, gamma, mu, and nu PVs (Pešut et al., 2021). Typically, HPVs belonging to the alpha, mu, and nu genera are known to induce a diverse spectrum of skin warts. Conversely, HPVs belonging to the beta and gamma categories are primarily linked to asymptomatic skin infections (Warburton et al., 2021). In addition to causing skin warts, certain alpha PVs have the ability to infect the mucosal epithelial tissue situated at the mucocutaneous junctions found in body openings, including the oral and anogenital regions (Warburton et al., 2021). Within the various genera of HPVs, there is a subset of viruses that are classified as oncogenic. Persistent infection with these oncogenic HPVs can potentially result in the occurrence of anogenital or oropharyngeal cancers (Warburton et al., 2021).

Out of the approximate 60 types of alpha-HPVs, 13 have been categorized and labeled as unequivocally or possibly cancer causing (HR). These alpha-HPV types, known for their HR nature, contribute to more than 95% of cervical cancers globally. The specific types considered HR include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 (Mirabello et al., 2018). Among the mentioned HPV types, each harbors various lineages and sublineages that demonstrate differences in intratypic genome sequences. These differences can range from 1.0% to 10% for lineages and from 0.5% to 1.0% for sublineages (Mirabello et al., 2018).

Specifically, HR HPV E6 aims to degrade the p53 tumor suppressor protein. By doing so, it prevents p53 from carrying out its normal cellular functions, such as orchestrating cell cycle arrest and triggering apoptosis in response to cellular stress signals (Lo Cigno et al., 2020). On the contrary, HR HPV E7 induces the pRb degradation, a protein known as the retinoblastoma tumor suppressor. This degradation process eliminates the E2F-mediated transcriptional activation of genes involved in the S-phase (Lo Cigno et al., 2020). Significantly, both HPV E6 and E7 are pivotal in inducing epigenetic changes within the chromatin. These changes occur through the alteration of regulation of gene expression or enzymatic activity of various epigenetic modifiers, encompassing histone deacetylases, histone demethylases, histone acetyltransferases, and histone methyltransferases (Lo Cigno et al., 2020).

The application of next-generation sequencing technologies in studying numerous primary cervical cancers has led to significant advancements. These recent findings indicate that the conventional model of HPV-induced carcinogenesis requires revision (Gao et al., 2019). A comprehensive review of numerous cases of cervical cancers positive for HPV16 and HPV18 has uncovered an interesting distinction. It has been observed that the incorporation of HPV within the human genome is more prevalent in HPV18-positive cervical cancers, occurring in the majority of cases. However, this integration is detected in only about 75% of HPV16-positive cervical cancers (Gao et al., 2019). Furthermore, research found that there is no specific preference for the HPV E2 gene alteration in cervical cancer. Breakpoints, which indicate the sites of genetic rearrangements, were observed to occur across the entire HPV genome in cervical cancer cases (Gao et al., 2019). Moreover, it has been identified that there are specific clustered hotspots where HPV integrates into the human genome. Notably, these integration sites often coincide with important cancer-related genes or are located in close proximity to them. This implies a possible connection between HPV integration and the dysregulation of crucial genes involved in cancer development (Gao et al., 2019). As a result, it has become evident that crucial human genes can play a role in the process of carcinogenesis. Consequently, the specific location(s) where HPV integrates into the human genome may hold greater significance than originally anticipated. This highlights the importance of studying the integration patterns and their potential influence on cervical cancer progression (Gao et al., 2019). The utilization of whole-genome sequencing has provided valuable insights into the intricate nature of the integration of HPV18 in the HeLa cell line. This analysis has revealed that the integration event takes place within a specific hotspot adjacent to the c-MYC oncogene, which is unique to HPV18. This finding highlights the complexity and specificity of the integration of HPV18 in the HeLa cell line (Gao et al., 2019). Also, the integration of HPV18 is linked to selective amplification of HPV18 sequences as well as neighboring human sequences. The total size of the disruption area resulting from this integration is estimated to be over 300 kb (Gao et al., 2019) (Fig. 1).

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FIG. 1.

Schematic representation of functional properties of HPV proteins.

There is poor correlation between HPV genetic relatedness and carcinogenicity: HPV31 and HPV35 are the types most closely related (genetically similar) to HPV16, but they are much less carcinogenic. At the same time, HPV18 is highly carcinogenic, but it is relatively distantly related to HPV16 and preferentially causes glandular lesions (Nelson and Mirabello, 2023).

Life Cycle

The life cycle of HPV, contingent on cellular differentiation, can be succinctly described in three stages as follows: 1.

The penetration of HPV into the basal cells located in the stratified epidermis.

HPV infection is primarily transmitted through direct contact between the skin or mucous membranes of individuals (Brianti et al., 2017). HPV targets and infects areas of the stratified epithelium that have been compromised, such as wounds or other forms of epithelial damage (Brianti et al., 2017). HPV infects epithelial cells by interacting with specific receptors on the cell surface, such as integrin α6. These receptors are plentifully present in basal cells and epithelial stem cells (Brianti et al., 2017).

In most cases, most of the HPV genome persists in an episomal condition within infected cells and premalignant lesions. It is believed that the virus infects keratinocytes and remains dormant, usually kept under control by the immune system (Christensen, 2016). Symptoms are not observed during either the transmission of HPV from one person to another or the transmission from an infected person to unaffected cells within the body (Christensen, 2016). Following resolution of the infection through immune system activity, it is plausible for the HPV to endure in a latent state within squamous cells that do not exhibit dysplasia. Consequently, Papanicolaou (Pap) smears have the potential to yield normal results. Nonetheless, it is imperative to maintain regular Pap screenings as per professional recommendations to effectively monitor any prospective alterations in cellular morphology (Christensen, 2016). In cases where the patient’s immune system is suppressed, the inactive virus has the potential to become contagious, leading to the possibility of basal epithelial cell differentiation in the infected individual (Christensen, 2016). Most HPV infections are temporary and exhibit no symptoms, and they are typically eradicated by the immune system (Christensen, 2016).

To generate virions and successfully conclude the infectious cycle, the HPV life cycle does not involve a lytic phase and instead relies on the final keratinocyte differentiation program as a necessary requirement (Ilahi and Bhatti, 2020; Pinidis et al., 2016). It is hypothesized that infection takes place when a microabrasion exposes the proliferative cell layer (Basal Stem Cells) to an HPV virion (Fisher, 2015).

After entering the cell, the viral DNA is in an unenveloped state and undergoes acidic compartments such as late endosomes and lysosomes (Fisher, 2015). The main role of the viral capsid protein L2 is to facilitate the transportation of the viral DNA to the nucleus by interacting with various cytoplasmic partners in a series of steps (Fisher, 2015).

In the initial phase within the basal cell layer, the viral DNA undergoes amplification to approximately 50–300 copies within each cell upon entering the nucleus (Fisher, 2015; Pinidis et al., 2016). Every protein encoded by the HPV genome is integral to the HPV life cycle [14]. The E1 and E2 viral proteins work together to commence the replication of viral DNA and establish viral genomes (Fisher, 2015; Mac and Moody, 2020). The HPV DNA persists in actively dividing the basal cell layer for an extended period of time at a relatively consistent copy number. In the S-phase of the cell cycle, the HPV DNA is replicated utilizing the host cell’s replication machinery (Gupta and Mania-Pramanik, 2019). Most antiviral strategies primarily focus on the maintenance phase of replication, given that persistent infection by HR HPV is the main risk factor for cervical carcinogenesis (Gupta and Mania-Pramanik, 2019). During the maintenance phase, replication takes place through either an ordered or random mechanism, influenced by the nuclear environment and the levels of E1 in the host cell (in the ordered mechanism, each episome is replicated once per cell cycle, while in the random mechanism, some episomes replicate multiple times while others do not) (Gupta and Mania-Pramanik, 2019). Extensive research has demonstrated the essential role of viral proteins E1, E2, E6, and E7 in both the establishment and continual maintenance of viral DNA episomes within host cells (Murakami et al., 2019).

The vital helicase function of the highly conserved HPV protein E1, operating in the 3′ to 5′ direction, plays a crucial role in HPV genome replication and is believed to be significant for the sustained maintenance of HPV (Fisher, 2015; Mac and Moody, 2020). The function of E1 is reliant on the hexameric helicase assembly at the origin of replication (ori) in collaboration with E2 (Fisher, 2015; Mac and Moody, 2020), which is entirely dependent on the cooperation between E1 and the host cell replication machinery, as they closely interact to enhance bidirectional HPV genome replication (Fisher, 2015). E2 plays a multifaceted role, serving as a crucial protein involved in both viral DNA replication and transcriptional control. This dual function is essential for the preservation of episomes (Zhang et al., 2019). E2 is thought to regulate the early promoter by exerting both activating and inhibitory effects on its own expression, along with that of E6, E7, and E1 (Fisher, 2015; Magalhães et al., 2021). E8^E2C represents a shortened form of E2 that seems to hold significance during the establishment phase. It functions to limit early genome amplification and inhibit HPV replication, ultimately contributing to the maintenance of a stable copy number. This reinforces the notion of E2’s crucial role in copy number regulation (Fisher, 2015). In addition, E2 has a distinctive function in tethering HPV genomes to mitotic chromosomes, guaranteeing the accurate separation of viral DNA as cells divide (Prabhakar et al., 2023). The trans-repressive role of E2 on the early promoter, which occurs post-HPV DNA integration, is believed to contribute to carcinogenesis by increasing the expression of oncogenes (Kalathil et al., 2020).

Crucially, the introduction of external E2 into cervical cancer cells hosting integrated HPV genomes lacking functional E2 genes reinstates the regulation of E6 and E7 oncogenes, leading to apoptosis or senescence. This demonstrates the persistence of apoptotic and senescence pathways, which are, however, inhibited by viral oncogenes in invasive cervical cancer (Fisher, 2015; Pinidis et al., 2016).

The E7 oncoprotein accelerates cell cycle advancement and enhances replication competence in basal cells by promoting the degradation of the pRb tumor-suppressor protein, and by interacting with a variety of cellular components, including the activation of CDK2 (Fisher, 2015; Pinidis et al., 2016). Likewise, the versatile oncoprotein E6 serves multiple functions, primarily incapacitating p53, but it also inhibits apoptosis and regulates several cellular processes, including immune evasion. Furthermore, it promotes an extended lifespan by inducing telomere maintenance through hTERT (Fisher, 2015; Pinidis et al., 2016).

Working in tandem, E6 and E7 induce substantial alterations in the epithelial transcriptome, fostering an environment conducive to finely tuned cell cycle progression that supports viral DNA maintenance and productive replication. Simultaneously, they safeguard against senescence, extending the lifespan of the host cell (Fisher, 2015).

In a wart, a secondary amplification stage takes place, giving rise to infectious virions (Fisher, 2015). As cells undergo differentiation and migrate from the basal layer to the suprabasal layers of the epithelium, there is a significant upsurge in the transcripts of E1, E2, E1^E4, E5, and E8. This phenomenon leads to substantial amplification of viral episomes (Fisher, 2015).

The viral oncogenes E6 and E7 significantly contribute to DNA amplification in this stage as they assist in establishing an environment conducive to the progression of the cell cycle and synthesis of DNA within the differentiated, postmitotic cells (Burley et al., 2020) (Fig. 2).

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FIG. 2.

High-risk HPV life cycle: From basal cells to disease progression. High-risk HPVs infect the basal cells in the ectocervix by accessing microwounds. These cells serve as an infection reservoir, maintaining the viral genome. As they divide, daughter cells migrate toward the surface. In lesions caused by high-risk HPV types, cells express E6 and E7 proteins, driving cell division, whereas mid-layer cells exhibit elevated proteins for genome amplification. Upper layer cells exit the cell cycle and produce L2 and L1 proteins for packaging viral genomes. Infection may also extend to other cell types, affecting disease progression and contributing to adenocarcinoma development at the cervical transformation zone and endocervix.

HPV Pathogenesis

In most instances of cervical cancers, the viral genetic material becomes integrated into the cellular genome, which facilitates the transformation of the infected cells (Hampras et al., 2014). During the integration process, viral DNA breakpoints induced by HPV E1, E6, and E7 proteins or oxidative stress contribute to the increased expression and translation of viral oncogenes, particularly E6 and E7 (Folliero et al., 2023). Available evidence indicates that infection with cutaneous HPV types elevates the likelihood of nonmelanoma skin cancer in both individuals with a functioning immune system and those with compromised immunity, possibly through an indirect mechanism (Hampras et al., 2014). One proposed mechanism of cutaneous HPV carcinogenic activity is the inhibition of UV-induced apoptosis (Hampras et al., 2014).

Most HPV infections are typically limited to a temporary duration and will be cleared spontaneously, making them of a transient nature (Sadri Nahand et al., 2020). Contracting various types of HPV types can lead to benign conditions that are frequently subclinical. However, they may progress to the development of papillomas or warts on the epithelial surface (Mac and Moody, 2020). Nevertheless, the prolonged infection with HR strains of HPV, which are classified as group I carcinogens and are responsible for cancers in the anogenital tracts and oropharynx, can give rise to the emergence of a premalignant condition referred to as cervical neoplasia (Mac and Moody, 2020; Sadri Nahand et al., 2020). The incorporation of HPV E7 and E6 oncogenes into the host genome is regarded as a critical step in the progression of cervical cancer (Sadri Nahand et al., 2020). Immune evasion is a significant factor in the persistence of HPV infection (Hatano et al., 2021). The prolonged infection with HR strains of HPV, characterized by the incorporation of HPV E7 and E6 oncogenes into the host genome, is regarded as a critical step in the progression of cervical cancer (Kombe et al., 2023). No detectable viremia or cytolysis is evident during the early stages following the primary HPV infection in the cervix, which means that inflammation is not readily observable, and the innate immune system remains inactivated (Ujma et al., 2019). The completion of the virus’s life cycle occurs within actively dividing cells, utilizing the host cellular machinery (Sadri Nahand et al., 2020). Upon establishing a persistent infection, it induces alterations in the secretion of inflammatory cytokines, leading to the infiltration of immune cells (Sadri Nahand et al., 2020). In older individuals experiencing persistent HPV infection, there have been observations of changes in immune system responsiveness and elevated systemic levels of inflammatory cytokines (Bhuyan et al., 2022). Clinical studies have indicated that individuals in this age bracket are more commonly diagnosed with cervical cancer and are prone to exhibit a resistant increase in cytokines, contributing to the tumorigenesis associated with HPV (Das et al., 2023). Inflammation constitutes a vital aspect of the intricate biological response initiated by the body’s tissues in reaction to detrimental stimuli, which can include pathogens, irritants, injured cells, extreme temperatures, radiation exposure, or autoimmune processes (Nakkala et al., 2021; Sadri Nahand et al., 2020). Persistent HPV infection can lead to alterations in the secretion of inflammatory cytokines, contributing to the infiltration of immune cells and chronic inflammation, which is closely linked to HPV-associated cervical cancer (Avila et al., 2023). Inflammation is a designed protective response that involves blood vessels, immune cells, and molecular mediators (Zhao et al., 2021). The onset of inflammation swiftly releases chemokines and cytokines, triggering the innate immune response of the host (Zhao et al., 2021). These mediators collaborate and aid in recruiting effector cells to the location of injury or infection (Zhao et al., 2021). If the stimulus persists continuously, the initial acute inflammation can evolve into a chronic state, and chronic inflammation is closely linked to the onset of cancer (Zhao et al., 2021).

However, the involvement of HPV infection in triggering chronic inflammation and the connection between chronic inflammation and HPV-induced cervical cancer remain subjects of debate and controversy (Kudela et al., 2021). The development of cervical cancer necessitates several factors, including viral interactions, host-dependent factors, and environmental influences (Kudela et al., 2021). Moreover, there is supporting evidence suggesting that the epigenetic regulatory mechanisms may result in the aberrant regulation of tumor-suppressor genes and the activation of oncogenes, promoting the malignant phenotype in cancer cells (Kudela et al., 2021). In this context, microRNAs function as crucial regulators controlling cell cycle progression, apoptosis, metastasis, and resistance to chemical treatments (Kudela et al., 2021) (Fig. 3).

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FIG. 3.

The pathogenesis and natural progression of high-risk HPV infection. In the initial stage, the virus enters the basal layer of the epithelium through a scratch or microinjury, initiating gradual proliferation. Although most infections resolve spontaneously, some may remain latent for an extended period. In the final stage, the genetic material of the virus integrates into the human genome, resulting in increased replication rates and ultimately contributing to the progression of cervical cancer.

HR or Oncogenic HPV Types

Based on epidemiological and molecular biological data, acquiring specific types of HPV stands out as the most prevalent risk factor contributing to the progression of cervical cancer (Muñoz-Bello et al., 2022). Over 200 HPV variations have been recognized, distinguished by genomic variations, and they are typically categorized into low-risk (LR) and HR types (Miyagi et al., 2019). This classification is rooted in the virus’s oncogenic potential and its tendency to induce cancer, which is linked to its presence in either benign or malignant cervical lesions (Orlando et al., 2012). LR and HR-HPV types exhibit distinct molecular disparities, and they also differ in terms of their infection duration within a host as well as their modes of transmission between hosts (Orlando et al., 2012).

The carcinogenic HR types encompass HR-HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82, indicating their association with cancer (Colpani et al., 2020). In the HR category, certain HPV strains are infrequently detected in cancers but are often found in squamous epithelial lesion cells (Miyagi et al., 2019). In the category of HR HPV infections, HPV16 and 18 stand out as the predominant types connected to cervical cancer, constituting roughly 60% and 10%, respectively (Colpani et al., 2020). Cancers affecting the cervix, vagina, vulva, as well as anal squamous cell carcinomas are primarily linked to HR HPVs, with HPV 16 being particularly noteworthy in this context (Cornall et al., 2013; Kombe Kombe et al., 2020).

LR HPV Strains

LR HPV types encompass LR-HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81, which are primarily associated with benign genital warts (Colpani et al., 2020). The presence of over 200 common LR HPVs leads to the development of various seemingly benign epithelial lesions, such as genital warts (caused by HPV 6 and 11), common warts (caused by HPV 2, 27, and 57), flat warts (caused by HPV 3 and 10), verrucas or myrmecia (caused by HPV 1), and numerous other skin lesions (Egawa and Doorbar, 2017; Kombe Kombe et al., 2020). Generally, the immune system tends to eliminate LR HPV types more rapidly compared with HR types (Orlando et al., 2012).

In the general populace, LR HPV infection is not generally regarded as a significant contributor to malignant transformation, and the connection between LR HPV and cancer is uncertain, except in cases involving individuals with weakened immune systems and specific genetic backgrounds (Egawa and Doorbar, 2017). However, research has demonstrated that the risks of developing cancers associated with HPV are elevated in diseases induced by LR HPV types (Colpani et al., 2020).

Studies indicates that the E7 protein found in HPV6 and HPV11 exhibits a reduced binding affinity for pRb compared with the E7 protein found in HR HPV types. This difference in binding affinity may be one of the factors contributing to the lower efficiency of malignant transformation by HPV6 and HPV11 (Ivancic et al., 2020). Furthermore, in HR strains, E7 is responsible for triggering pRb degradation facilitated by the proteasome, thereby releasing the transcription factor E2F to drive cells into the S phase. In addition, exclusively HR E6 has the capability to facilitate the degradation of p53 through an E6AP-dependent mechanism, which compromises the host cell’s capacity to effectively complete cell cycle checkpoints (Ivancic et al., 2020). Both HR and LR HPV strains possess the ability of E6 to interact with p300/CBP, preventing the process of acetylating p53. However, HR E6 exhibits a stronger binding affinity to p300/CBP compared with LR E6 (Ivancic et al., 2020).

Immune Interactions

Around 80% of individuals experience anogenital HPV infection at some stage in their lives. However, these infections are predominantly cleared by the immune system of the host, a process that may extend over 1–2 years from the initial exposure to the virus. Only a small percentage of individuals who have contracted the virus go on to develop HPV-related tumors (Lo Cigno et al., 2020). The persistent presence of E6 and E7 in tumors implies their involvement in both the development and sustenance of these cancerous growths (Kajitani and Schwartz, 2022). The activity of E6 and E7 likely exerts significant control over cell proliferation, a function typically governed by proteins such as p53 and pRb. This control allows for the buildup of genetic mutations and abnormalities in chromosomes, ultimately contributing to the onset of cancer (Kajitani and Schwartz, 2022).

The latency phase of HPV infection typically spans about 10 years, during which the host’s immune response significantly influences the advancement or decline of cervical HR HPV infection (Song et al., 2015). The virus is naturally cleared by a robust and effective immune response. Conversely, a weakened immune response often initiates the pathological process, leading to the development of CIN and eventually carcinogenesis (Song et al., 2015).

Infection with HR HPV prompts the mobilization of immune cells to the dermal layer (Song et al., 2015). T lymphocytes, macrophages, KCs, Langerhans cells (LCs), natural killer (NK) cells, dendritic cells (DCs), and B lymphocytes within the squamous epidermis all contribute significantly to orchestrating the immune response to infection (Aghbash et al., 2022) (Fig. 4). HR HPV infection has the potential to enhance immune system resistance, but it may also create a microenvironment that is susceptible to subsequent infections, thereby facilitating the progression of CIN (Aghbash et al., 2022). The proposed and verified mechanisms include the following: To begin with, HR HPV remains latent for an extended period, and its replication and assembly do not induce cell lysis or cytopathic host cell death (Song et al., 2015). Next, HR-HPV interferes with the synthesis of interferon (IFN) by means of the E6 and E7 oncoproteins, which disrupt IFN signaling pathways (Song et al., 2015). Moreover, HR-HPV infection prompts the infiltration of regulatory T cells (Tregs) and the release of interleukin (IL)-10, along with the production of transforming growth factor β (Song et al., 2015). Furthermore, infected cells exhibit reduced expression of major histocompatibility complex class I (MHC1), compromising the function of cytotoxic T lymphocytes (CTLs) (Song et al., 2015). Finally, the accumulation of nonfunctional CD4 and CD8 T lymphocytes can be induced in stage II/III CINs (Song et al., 2015).

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FIG. 4.

Schematic illustration of innate and adaptive immune responses against HPV. During the initial phase of infection, innate immune cells, including natural killer cells, macrophages, and dendritic cells, initiate the immune response by neutralizing HPV and releasing cytokines. Particularly, dendritic cells function as antigen-presenting cells following virion destruction. During intracellular processes, they present specific peptides on their surface, which are then recognized by the major histocompatibility complex I and II molecules. This process ultimately triggers both cellular and humoral immune responses, which persist for an extended duration.

Simultaneously, the oncogenic stimuli initiated by HPV oncoproteins compel host cells to enhance their innate immune response against the virus (Lo Cigno et al., 2020). Nevertheless, HPVs have developed tactics to circumvent the host’s antiviral immune response, enabling them to successfully finish their viral life cycle and endure within the host cell (Lo Cigno et al., 2020).

Vaccines

Roughly 60% to 70% of females who become infected with HPV develop a detectable antibody response specific to the HPV L1 capsid protein, characterized by epitopes that become apparent in their serum. This response serves as a less sensitive indicator of the overall exposure to HPV over time (Beachler et al., 2016). In theory, these naturally acquired polyclonal antibodies could potentially provide protection against subsequent infections with the same type of HPV (Beachler et al., 2016). Indeed, this natural HPV immunity can be considered a factor in cost-effectiveness models when assessing the advantages of administering prophylactic HPV vaccines to older individuals (Beachler et al., 2016).

Six licensed prophylactic HPV vaccines are available: three bivalent, two quadrivalent, and one nonavalent vaccine (Williamson, 2023). These include the 2-valent HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18v; Cervarix, GSK), the 4-valent (4vHPVv) (6,11,16,18), and the 9-valent (9vHPVv) (6,11,16,18,31,33,45,52,58) aluminum hydroxyphosphate sulfate adjuvant vaccines (Gardasil, Merck) and a bivalent HPV vaccine (HPV-16 and HPV-18) (Cecolin, Xiamen Innovax Biotech Co., Ltd., Xiamen, China) (Khan et al., 2023). There is limited information available regarding the newer HPV vaccines. Two recently developed Chinese vaccines underwent testing in a randomized, blinded, noninferiority phase III trial to assess the effectiveness of their innovative four-valent and nine-valent HPV vaccines and were demonstrated to be equally effective as GARDASIL in terms of both immune response and safety (Williamson, 2023). These vaccines use eukaryotic cells or Escherichia coli to produce HPV L1 VLPs (Kheirvari et al., 2023). Research has shown that these vaccines can be effective in preventing not only genital warts but also high-grade vaginal, anal, cervical, and vulvar cancers and precancerous lesions in women. In addition, they have demonstrated efficacy in preventing cancers, precancerous lesions, and genital warts in men (Chaturvedi et al., 2018).

The 2-valent HPV-16/18 vaccine is designed to combat two specific types of HPV, 16 and 18, which collectively contribute to up to 70% of cervical cancers. Moreover, it has demonstrated cross-protection against HPV types 31, 33, and 45, which are the subsequent most prevalent types of HPV associated with cervical cancer (Mehanna et al., 2019). HPV vaccines work via VLPs, which are noninfectious assemblies of the L1 HPV capsid protein. VLPs induce a strong neutralizing antibody response, preventing HPV uptake by cervix basal cells. The vaccines provide subtype-specific protection and cross-protection against other HPV types (Illah and Olaitan, 2023). The existing Gardasil HPV vaccine has proven to elevate the population of NK cells following immunization. This increase is linked to heightened levels of receptors such as NKp30, NKp46, NKG2D, and ILT2 in NK cells. This suggests the involvement of additional pathways, extending beyond the augmentation of neutralizing antibodies, in contributing to the effectiveness of the vaccine (Amador-Molina et al., 2013; Akhatova et al., 2022).

A comprehensive examination of real-world experiences with the 4vHPV vaccine on a global scale demonstrated a reduction of over 90% in HPV 6/11/16/18 infections, a 90% decline in genital warts, a 45% decrease in low-grade cytological cervical abnormalities, and an 85% decrease in high-grade cervical abnormalities among women in the younger age groups who are the primary targets of national immunization programs in nine countries (Maver and Poljak, 2018). The efficacy of HPV vaccines is influenced by several factors, including vaccine coverage, the birth cohorts’ age targeted for vaccination, the implementation of comprehensive programs in older age groups, the time between program commencement and outcome evaluation, and the duration of follow-up. These elements collectively contribute to the overall impact of HPV vaccination programs (Maver and Poljak, 2018). Nevertheless, a documented decline in the prevalence of HPV infections and genital warts among unvaccinated women and men during the vaccine era suggests the possibility of herd protection (Maver and Poljak, 2018).

Up to this point, there has been limited exploration into the impact of vaccination on oral HPV infection (Mehanna et al., 2019; Nielsen et al., 2021). It is crucial to note that all studies have utilized oral rinse for assessment, and there have been no investigations that simultaneously examine HPV prevalence using both oral rinse and tonsil tissue, or evaluate the vaccine’s impact on HPV prevalence in tonsil tissue, which is the primary site associated with oropharyngeal cancer (Mehanna et al., 2019). In addition, there is a lack of research examining the effectiveness of vaccination initiatives in reducing oral HPV prevalence among children, and no studies have explored the protection of men against oral HPV infection through the potential herd effect resulting from a national vaccination program targeting females exclusively (Elit et al., 2022; Mehanna et al., 2019) (Fig. 5).

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FIG. 5.

Characteristics and content of HPV prophylactic vaccines.

Common Treatments

There are limited data available regarding the comprehensive treatment of cervical diseases associated with HPV (Kechagias et al., 2022). The main objective of treatment is to relieve symptoms, eliminate wart-infected transformation zones, and decrease the likelihood of subsequent invasive cervical cancer (Kechagias et al., 2022). Managing and treating diseases associated with HPV greatly depend on several factors, such as the particular HPV types involved, the variety of treatment options available, and the stage or progression of the disease (Bosch et al., 2013; Gupta et al., 2018). These critical factors influence the approach taken to effectively manage and treat HPV-related conditions (Bosch et al., 2013).

To address external genital warts resulting from nononcogenic HPVs, the common recommendation is the use of trichloroacetic acid, sinecatechins, podophyllotoxin, and imiquimod at concentrations ranging from 80% to 90% (Sindhuja et al., 2022). Furthermore, in specific cases, other limited therapies such as photodynamic therapy, intralesional/topical IFN, and 5-fluorouracil may be considered for managing external genital warts resulting from nononcogenic HPVs (Gilson et al., 2020) (Table 1).

It is typically recommended to use surgical methods to address cervical precancerous lesions induced by oncogenic HPVs. These methods may include laser therapy, loop electrosurgical excision procedure, electrosurgery (such as cone biopsy or conization), cryosurgery (freezing), as well as excisional procedures with local anesthesia (Lee et al., 2022). Numerous studies have demonstrated that the choice of a specific surgical method has minimal impact on the likelihood of recurrence in managing cervical precancerous lesions attributed to oncogenic HPVs. Therefore, the selection of treatment may be contingent on the accessibility of the method and the physician’s discretion (Cusimano et al., 2019) (Table 2).

Current treatment approaches for cervical cancer frequently involve a combination of adjuvant or neoadjuvant chemotherapy, radiation therapy, and often a hysterectomy. These strategies aim to effectively manage and treat the disease while considering its stage and extent (Miriyala et al., 2022). Research has indicated that chemotherapy is an important and efficient choice for treating cervical cancer, applicable across a spectrum of stages, ranging from locally advanced to metastatic cases (Gadducci and Cosio, 2020; Miriyala et al., 2022). In the past, cisplatin-based chemotherapy (CRT) was the preferred treatment for women with distant metastases or recurrent cervical cancer (Do et al., 2021). Currently, the widely acknowledged standard treatment for invasive cervical cancer is definitive radiation therapy with concurrent CRT, even though it comes with a somewhat higher risk of recurrence (estimated at 25–40%). This treatment approach is considered the gold standard for managing this condition (Khairkhah et al., 2022). Chemotherapy can be administered either as postoperative adjuvant therapy or as neoadjuvant chemotherapy before surgery in the treatment of cervical cancer. Interestingly, meta-analyses suggest that both approaches yield similar overall survival rates, providing flexibility in the choice of treatment strategy for individual patients (Lorentzen et al., 2022). Recent investigations and analyses suggest that combining various chemotherapy agents, including capecitabine, vinorelbine, pemetrexed, paclitaxel, irinotecan, ifosfamide, topotecan, and S-1, can enhance the efficacy of cervical cancer treatment. The goal of this combined therapy approach is to enhance outcomes for individuals diagnosed with cervical cancer (Duenas-Gonzalez and Gonzalez-Fierro, 2019). The choice of these drugs can be determined according to the specific condition of each patient (Duenas-Gonzalez and Gonzalez-Fierro, 2019).

Hysterectomy is a surgical intervention that entails the extraction of the uterus (Kumar and Vijan, 2021). Radical hysterectomy, a procedure that encompasses the removal of the uterus along with the parametrium and the upper part of the vagina, has been demonstrated to be the most efficient approach (Kumar and Vijan, 2021). Nonetheless, it is crucial to emphasize that a hysterectomy can have adverse effects on fertility and may result in physical and psychological health challenges that can affect a patient’s overall quality of life (Elsaied et al., 2020) (Table 3).

Current research has explored the potential advantages of integrating checkpoint inhibitors into existing cervical cancer treatments. Immune checkpoint pathways, particularly cytotoxic lymphocyte antigen 4 and PD-1, can inhibit the body’s immune response and diminish T cell function (Chitsike and Duerksen-Hughes, 2020). Monoclonal antibodies such as pembrolizumab, nivolumab, and ipilimumab have been created and sanctioned by the Food and Drug Administration to specifically target the PD-1 axis for the treatment of cervical cancer (Liu et al., 2019).

Discussion

HPV infection represents a significant global health concern due to its widespread prevalence and association with various cancers. HPV is a circular, double-stranded DNA virus with over 200 identified types, making it the most prevalent sexually transmitted infectious agent worldwide. The HPV life cycle involves infiltration into basal cells of the epidermis, minimal gene expression, and productive replication in differentiated cells. Integration of HPV into the host cell’s DNA contributes to cellular transformation and malignant progression.

Immune interactions play a pivotal role in determining the outcome of HPV infection. Innate immunity, mediated by cells such as macrophages, DCs, and NK cells, serves as the first line of defense. Subsequent adaptive immune responses involving T and B lymphocytes are crucial for eliminating infected cells and generating long-term immunity. However, the balance between clearance and persistence of HPV infection is determined by the effectiveness of the host immune response, highlighting the importance of a well-coordinated immune response.

Prophylactic HPV vaccines have emerged as a cornerstone of prevention efforts, demonstrating efficacy in preventing genital warts, high-grade precancerous lesions, and cancers. Available vaccines offer protection against a range of HPV types, providing options for both females and males. It is essential to note that HPV vaccination does not treat existing infections but prevents future infections and associated health risks.

Effective management and treatment of HPV-related diseases are vital for reducing morbidity and mortality. Surgical interventions, chemotherapy, and radiation therapy play integral roles in addressing precancerous lesions and cervical cancer. In addition, the integration of checkpoint inhibitors into existing treatments represents a promising avenue for enhancing therapeutic outcomes and overcoming immune evasion mechanisms used by HPV.

In conclusion, this comprehensive review provides insights into the genetic, immunological, and clinical aspects of HPV infection and its associated diseases. By elucidating these aspects, evidence-based strategies for the prevention, diagnosis, and treatment can be informed. Collaborative efforts across disciplines are essential for advancing our understanding of HPV and mitigating its impact on global public health.

Conclusion

HPV poses a significant public health challenge, demanding a nuanced understanding of its life cycle, immune response dynamics, and available preventive measures. The advent of prophylactic HPV vaccines has been instrumental in curbing the prevalence of genital warts, cervical cancer, and related diseases, emphasizing their pivotal role in public health strategies. Encouraging vaccination, particularly during adolescence or early adulthood, holds promise in reducing HPV infection rates and averting associated health risks, underscoring the importance of proactive immunization efforts.

Comprehensive approaches that integrate vaccination programs, awareness campaigns, and evidence-based interventions are crucial for effectively addressing HPV impact. By fostering collaboration across disciplines and prioritizing preventative measures, we can advance toward the goal of minimizing the burden of HPV-related diseases on a global scale.

Author Confirmation Statement

Ms. Nikmanesh, Ms. Mirbagheri, Ms. Asadsangabi, Mr. Fattahi, Mr. Safarpour, Mr. Fallahzade Abarghooee, Ms. Shamsdin, and Mr. Akrami are from Shiraz University of Medical Sciences (Shiraz, Iran); Mr. Moravej is from Fasa University of Medical Sciences (Fasa, Iran); Ms. Hosseini is from the University of Kurdistan (Shiraz, Iran); Mr. Saghi is from Larestan University of Medical Sciences (Larestan, Iran) and Mashhad University of Medical Sciences (Mashhad, Iran), and Dr. Nikmanesh is from Shiraz University of Medical Sciences (Shiraz, Iran), all where education and research are the primary functions.