Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 Contents lists available at ScienceDirect Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn 1 The natural history of human papillomavirus infection a, b, *, Maria Brotons a, c, Silvia de Sanjose n a, b Miguel Angel Pavo Biom Cancer Epidemiology Research Programme, Institut d’Investigacio edica de Bellvitge (IDIBELL), Catalan Institute of Oncology, L'Hospitalet de Llobregat, Spain n Biom Centro de Investigacio edica en Red en Epidemiologia y Salud Pública CIBERESP, Barcelona, Spain c n Biom Centro de Investigacio edica en Red en Oncologia CIBERONC, Barcelona, Spain a b a b s t r a c t Keywords: Natural history HPV Risk factors Cervical cancer Acquisition Persistence Human papillomavirus (HPV) is a small double-stranded DNA virus that commonly infects humans. The oncogenic characteristics of HPV derive from the oncoproteins E6 and E7 that act inhibiting p53 and pRB tumor suppressors. About 5% of all cancers worldwide are attributable mainly to those known as high-risk, including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Infection with HPV is common after sexual initiation, but the majority of HPV infections do not cause symptoms or disease and are cleared within 12e24 months post-infection. Only a small fraction of those infections that persist or progress to a preneoplastic lesion result in cancer. Persistence of HPV infection is needed to start the oncogenic process. Clearance of infection is common in young adults. Viral load and viral type are the main cofactors for progression from infection to cervical intraepithelial lesions and cancer. Smoking, hormonal exposure, and HIV are additional exposures that increase the risk of progression to cancer. The adverse health effects of HPV infections can be largely controlled through vaccination and screening. © 2017 Published by Elsevier Ltd. Biome dica de Bellvitge (IDIBELL), * Corresponding author. Cancer Epidemiology Research Programme, Institut d’Investigacio d'Oncologia, Av. Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Spain. CIBERESP, Institut Catala ). E-mail address: s.sanjose@iconcologia.net (S. de Sanjose http://dx.doi.org/10.1016/j.bpobgyn.2017.08.015 1521-6934/© 2017 Published by Elsevier Ltd. S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 3 Introduction Human papillomavirus (HPV) has been identified as the cause of approximately 5% of all cancers worldwide [1]. HPV infection is associated with virtually all cervical cancers and a significant proportion of anogenital (vulvar, vagina, penile, and anal) and oropharyngeal cancers [2]. HPV infection is also associated with other skin and mucosal lesions such as warts and benign papillomas [3]. The majority of HPV infections do not cause symptoms or disease and are cleared within 12e24 months post infection. Only a small fraction of those infections that persist or progress to a preneoplastic lesion result in cancer. Each infection stage and behavior may be influenced by environmental, host, and viral factors, the knowledge of which is essential to understand the natural history of the HPV infection and to develop new tools for improving the management of HPV-positive lesions and the prevention, early detection, and treatment of HPV-associated cancers. HPV infects both men and women, although the burden of attributable disease is much larger in women because of the high susceptibility to HPV infection of cervical cells [1]. Thus, the accumulation of research data is far larger for this site as it is our understanding of the natural history of cervical HPV. We recommend specific reviews on HPV in other sites [4,5]. In this chapter, we will review the natural history of genital HPV infections focusing on the biological characteristics of HPV and factors intervening in its acquisition, clearance, persistence, and progression to human cancer and particularly cervical cancer. Other chapters will provide detailed information on HPV worldwide burden of related disease and relevant interventions to prevent the adverse effects of HPV infections. HPV classification More than 200 HPV genotypes have been identified in the last century and grouped in different genera (Alpha-, Nu-/Mu-, Beta- and Gamma-papillomavirus) according to the viral genome structure and tropism to human epithelial tissues [6e8]. The Alpha genus includes genotypes that have been described to cause cancer, while Beta- and Gamma-papillomavirus infection courses are generally asymptomatic, but immunosuppression states (i.e. organ graft, HIV infection, epidermodysplasia verruciformis disorder among others) can trigger these types to produce cutaneous papilloma or increase the predisposition to skin cancer [9]. Twelve types (16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), also known as high-risk types, have been classified as carcinogenic to humans according to the International Agency for Research on Cancer (Table 1). Low-risk types including HPV6 or HPV11 generally cause benign diseases such as genital warts [10], while other types classified as probably or possible carcinogenic are rarely found in large series of cancers or are associated with additional factors, so their oncogenicity remains to be clarified [11]. HPV genome Despite the papillomavirus family representing a remarkably heterogeneous group of viruses, they share the same genome structure and organization [12] (Fig. 1). A circular double-stranded DNA genome of approximately 8 kb is structured into three main regions: (i) The early region (E) encodes genes that Table 1 Broad classification of human papillomavirus (HPV) by oncogenic risk and associated diseases according to the International Agency for Research on Cancer Evaluation. Human papillomavirus Genotypes Associated disease High risk or oncogenic HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 HPV 6, 11 HPV 68 HPV 5, 8 Cervical, anal, vaginal, vulvar, penile, and oropharyngeal cancer and associated precursor lesions Genital warts, recurrent respiratory papillomatosis Cervical cancer Squamous cell carcinoma of the skin in patients affected by epidermodysplasia verruciformis Uncertain Low-risk types Probable carcinogenic Possible carcinogenic Possible carcinogenic HPV 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, and 97 4 S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 URR: origin of replication, transcription factor-binding sites and gene expression control URR E1: Viral DNA replication and transcription E7 E6 E2: Viral DNA replication, apoptosis, transcriptional repressor of E6/E7 E4: viral DNA replication L1: Major capsid protein L2: Minor capsid protein HPV16 L1 E1 dsDNA 7906 bp L2 E5 E5: cell proliferation, alteration of signaling pathways (EGFR), immune recognition ( MHC) and apoptosis E6: p53 degradation, alteration of cell cycle regulation, apoptosis resistance chromosomal instability and cell immortalization (TERT) E4 E2 E7: pRB degradation, re-entry into S-phase cell cycle, p16 realize and overexpression, chromosomal instability Fig. 1. HPV 16 structure and viral proteins. are necessary for the viral cycle and with an important role in cell transformation (E1, E2, E4, E5, E6, and E7). (ii) The late region (L) encodes the L1 and L2 capsid proteins. (iii) The upstream regulatory protein, referred also as the long control region, is a noncoding region containing the replication origin and transcription factor-binding sites that contribute to regulate DNA replication by controlling the viral gene transcription. E6 and E7, together with E1, E2, E4, and E5, expression are essential for viral genome replication and virion synthesis and release, but they also play a key role in cell transformation [9]. HPV life cycle HPV life cycle begins with the infection of the basal layer through microtraumas that compromise the epithelial barrier [13] (Fig. 2). HPV genome is maintained at low copy number in the infected host basal cells. Upon differentiation of epithelial cells, the virus replicates to a high copy number and expresses the capsid genes (L1 and L2), resulting in the production of new progeny virions that are released from the epithelial surface. For persistence, HPV needs to infect basal cells showing stem celllike features that are still able to proliferate [14]. This phenomenon is far less common in HPV low-risk types. The epithelial transition zones, such as the endo-/ectocervix and anorectal junctions, are regions more susceptible to carcinogenesis by high-risk HPV types [15]. High-risk types are more prone to activate cell proliferation in basal and differentiated layers promoting the transition from a productive infection to an infection, which is unable to complete the viral life cycle but is able to activate several pathways essential for the epithelial transformation. One plausible explanation of the increased oncogenic capacity of the high-risk types and particularly the HPV16 type resides in the activity of the E6 and E7 oncoproteins. Although the E6 and E7 activity is present in high- and low-risk types, their role in low-risk types is limited to increase the viral fitness and viral production and it is largely insufficient to trigger the development of preneoplastic lesions and cancer [16]. High-risk HPV types have developed several mechanisms to avoid host immune response, which is important for viral persistence and progression to HPV-associated neoplastic diseases. One of the first strategies to avoid detection is to maintain a very low profile [17,18]. The HPV cycle is exclusively intraepithelial and not lytic, therefore preventing the associated pro-inflammatory signal. As a result, the recruitment of antigen-presenting cells such as Langerhans cells (LC) and the release of cytokines that mediate the immune response are absent or very low after the HPV infection. Other mechanisms of HPV immune evasion include the regulation of the interferon signaling, inhibition of LC by the E6 and E7 activity, inhibition of adherence molecules such as the CDH1, and modulation of intracellular signaling pathways. HPV-mediated carcinogenesis E6 and E7 early proteins conduct their main role in the carcinogenic process through the inhibition of p53 and pRB tumor suppressors [19,20]. E6 functions include also the activation of the telomerase S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 Fig. 2. Schematic representation of the HPV infection in cervical mucose and its different potential squamous intrepitelial lesions. 5 6 S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 activity and deregulation of pathways involved in immune system response, epithelial differentiation, cell proliferation, and survival signaling. Besides cell cycle deregulation and proliferation, E7 enhances genomic instability and promotes the accumulation of chromosomal abnormalities. The deregulation of the cell cycle, the activation of the telomerase activity, and genomic instability create a favorable environment for the epithelial cell transformation. HPV integration can also drive the carcinogenic process through the inactivation of the E2 expression, the main inhibitor of E6 and E7, and the disruption of host genes because of the viral sequence insertion [21]. The carcinogenic process, initiated with the E6 and E7 activation, needs to be complemented by the accumulation of additional alterations in the host gene to lead to the invasive cancer phenotype. The integrated genomic analysis conducted by The Cancer Genome Atlas Consortium identified genes that were significantly mutated in cervical and head and neck HPV-associated tumors [22,23]. Interestingly, a high percentage of the identified mutations show a pattern compatible with the activity of APOBEC, an innate immune system that can bind and edit the viral DNA, restricting the viral infection. APOBEC3B can be activated, in turn, by E6 and E7 oncoproteins [24,25]. Thus, APOBEC could be an important source of mutagenesis in HPV-associated cancers, as has been reported in multiple human cancers [26]. Viral genetic variation, beyond the HPV genotype, could explain in part differences in clearance, persistence, and risk to develop cancer among infections positive for the same type. Papillomaviruses are classified into types depending on L1 sequencing, defining a new type when its genome differs by at least 10% from that of all other classified types [27]. HPV isolates of the same type that differ by less than 10% in the genome sequence are classified in variant lineages and sublineages. These variants have shown differences to be associated with the risk of cancer. For example, women with a HPV16 non-A variant (B, C, and D) were consistently at an elevated risk of cervical cancer compared to women with other variants. Moreover, D2/D4 sublineages were more common in glandular cervical lesions, while A1/A2 variants were identified in the large majority (75.4%) of the squamous cell carcinomas of the cervix [27,28]. Growing evidence suggests that epigenetic alterations directly or indirectly related with the E6 and E7 activity are common events during the early steps of epithelial malignization and have been described as potential biomarkers for cervical cancer [29,30]. HPV prevalence, acquisition, and clearance in the population Fig. 3 summarizes cervical HPV DNA prevalence by age observed after pooling existing data worldwide [31]. The figure refers to prevalence, which results from the combined effect of incidence (acquisition) and duration of infection (clearance/persistence). The majority of anogenital HPV infections are acquired through sexual contact, and acquisition is strongly determined by the accumulation of sexual partners and their respective sexual behavior [32]. A new infection can be detected soon after the first sexual contact with an infected partner, and most of them will be detectable within 1 year of exposure [33,34]. As a result of this high transmission, HPV infections are very common in young women depicting the peak in prevalence observed in the figure, which generally takes place around 20e25 years of age. An abrupt decline follows as a result of frequent clearance and lower exposure to new partners. This pattern is consistent in populations all over the world and confirms the sexual transmission as the main mode of transmission. Variations to the left/right of the peak age will relate to the average age of the sexual initiation in a given population. The intensity of the peak will be modulated by the average number of sexual partners interchange in men and women. The shape of the curve could also be affected by screening practices. Infections leading to cervical intraepithelial lesions may be detected through screening and thus its natural evolution be modified by treatment. After this period, prevalence of infection remains relatively stable at the range of 5e10%. In some countries, a second peak is observed after menopause. Reasons for this late increase are not well understood [16,31,35]. One of the first prospective studies to explore HPV acquisition was conducted in a cohort of 1610 women aged 15e85 years who were HPV negative at baseline in Colombia. Women were followed every 6 months for about 5 years [36,37]. HPV acquisition was present in cohorts of all ages but with a varying intensity, being highest in younger cohorts with a cumulative incidence of 0.42 in S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 7 Fig. 3. General pattern of the HPV DNA prevalence in the exofialted cervical cells in healthy women by age and main determinants of the shape of the curve. women aged 15e19 years in contrast to a cumulative incidence of 0.12 in women aged >44 years (Fig. 4). Acquisition of new partners and having had more than one sexual partner were strong determinants of new infections. On the contrary, having a long-standing first sexual relation decreased the risk of new infection. Consistently [38], in a cohort of UK students, the authors identified a significant 1.99 risk increment for new HPV infections (95% CI 1.46e2.72) among those women who had multiple sexual partners compared to monogamous women. Two concomitant studies involving women internet daters in Canada showed that reporting new and/or multiple partners in the past 6 months was positively associated with increased incident HPV [39,40]. A recent analysis of the placebo group of women participating in a vaccine clinical trial resulted in an overall detection of new HPV infections of 20.61 (95% CI 18.47e22.99) per 1000 personmonths during a 6-year follow-up. The incidence further increased by 88% among women with more than one sexual partner as compared to those having only one partner. HPV16 was the most common new infection with an incidence rate per 1000 person-months of 4.16 (95% CI 3.44e5.02) [41]. Following women over time has demonstrated that up to half of the HPV infections clear within 6 months and that the great majority (>90%) clear within a few years after acquisition [42,43]. Innate and adaptive immune responses are interplayers in the resolution of such common infections [16]. A Th1 pro-inflammatory response in the genital tract has been suggested as a potential mechanism for clearance [44], but cell-mediated immune response may be the most common mechanism. Shannon et al. [45] studied in a set of 65 African/Caribbean women the vaginal immunological environment by HPV clearance and persistence. Participants who cleared HPV had a significantly higher absolute number of endocervical LC (5018 cells/cytobrush) than either HPV-negative women (635 cells/cytobrush, p ¼ 0.015) or those with persistent HPV infection (180 cells/cytobrush, p ¼ 0.023). However, no association between prevalent HPV infection and genital inflammatory cytokines nor with endocervical CD4þ T cell numbers or presence of highly susceptible CD4þ T cell subsets such as those expressing CCR5 or CD69 were identified in this study. 8 S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 Fig. 4. Cumulative incidence of new HPV infections in 5 year follow up by age group in Colombia. Adapted from Bosch et al. Vaccine 2008. Consistent with others, they observed a differential pattern of the vaginal microbiome among those clearing the infection with more abundant Lactobacillus spp. [46,47]. Others have identified bacterial vaginosis associated with persistence of HPV infections among pregnant women [48]. More data are needed to have a full understanding of how HPV infections are modulated by the vaginal environment. HPV antibodies acquired through natural infection are observed in a limited number of infected people. In the US, among unvaccinated women aged 20 years, only 20% had detectable antibodies to HPV16 [49]. A systematic review of the acquired natural immunity against subsequent genital HPV infection identified a range of seroprevalence estimates against HPV16 of 6.2%e45.5% with a relative modest protection for HPV16 reinfection of 0.72 (0.62e0.82) and thus unlikely to play a major role in clearance [50]. Data from vaccine trials have shown a protective but moderate impact of natural immune response against cervical disease [51,52]. Consistent with this moderate effect, a recent followup study of 1848 women attending cervical cancer screening in Slovenia exploring the natural antibody response against HPV16 showed that baseline anti-HPV16 antibodies were not associated with clearance of HPV16 infection at follow-up (odds ratio for clearance ¼ 0.8; 0.3e1.9) [53]. Overall, the natural immune response is clearly insufficient to control for new infections and is far lower when compared to the high levels of seroresponse and the high efficacy observed against persistent infections after HPV vaccination [16]. In some circumstances, after follow-up of a positive HPV test, HPV may be undetected simulating a cleared infection. It is now accepted that HPV infection may be latent and controlled by a cellular immune surveillance environment in which viruses are kept in very low copy numbers escaping its detection. Reactivation may occur under moderate (i.e., menopausal state, aging) to relevant immunosuppressive situations (i.e., organ graft) [54] with or without hormonal influence). This reactivation could explain the second peak in HPV prevalence observed in some population in postmenopausal women. HPV persistence and progression to cervical intraepithelial lesions and cancer Persistent carcinogenic HPV infections clearly predict the risk of cervical cancer in women [55,56]. Persistence is not homogeneously measured but is a very relevant concept as many populations un~ oz et al. defined dergoing screening using HPV tests will rely on measures of persistent infection. Mun persistence as those infections that last more than the median duration but this concept is relevant for natural history studies. Others define persistence as those having two positive HPV DNA consecutive tests with undetermined time interval [37,57]. Time interval between two measures affects the persistence estimate as many infections will be cleared by year 2. Marks et al. compared 12 versus 24 S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 9 months in defining a persistent infection and showed substantial increases in the specificity of the combined two HPV tests using 24 months for the detection of cervical lesions [57]. In many screening programs, a 12-month test repetition is recommended among those who are HPV-positive at first screening with a negative cervical cytology. Although 12 months may be a too short interval, it may provide some “safety window” as first infection may have a long-standing prevalence. For newly acquired infections, a longer interval may be more efficient. Irrespective of the time window, major determinants of HPV persistence are HPV type and viral load at first detection. It remains unclear whether age is a key element for persistence. However, in the ~ oz et al. previously described, median duration of HPV incident infection was prospective study by Mun higher for high-risk HPV types than for low-risk types and for HPV16. Women younger than 30 years had a longer mean duration for HPV16 infections of 16.6 months, while women >30 years had a significantly shorter duration of 9.5 months. Others suggest that persistence increases with increasing age [58]. The presence of more than concomitant HPV infections, a phenomenon very common in younger populations, is reported to not influence the duration of infection [59]. The low proportion of women who are not able to clear the infection are those at risk of developing cervical cancer. Soon after the HPV infection is established, cellular changes can be observed in the cervical exfoliated cells. Persistent infections can result in different grades of squamous intraepithelial lesions that ultimately can lead to high-grade lesions and cancer in an average of 5e14 years if undetected and untreated [60] (Fig. 2). Within the types involved in the carcinogenic process, persistent infection with HPV16 is most commonly associated with a faster progression to cervical lesions and invasive cervical cancer [55,56]. It is noticeable that progression in HPV16 infection is not affected by strong-acting DNA variations of the virus [61]. HPV16 is involved in over 60% of all cervical cancers but also in other HPV-related cancers as shown in Fig. 5 [62e66]. Other types including HPV18, 45, 31, and 33 are also commonly detected in cancer specimens but their lower contribution suggests a different natural history as the one of HPV16. As a consequence of these observations, detection of HPV16 in women aged 30þ is considered in many settings an indication of immediate colposcopy for screening of cervical cancer [67], while detection of other high-risk types may be followed by a second triage test. In addition to the viral characteristics, environmental or exogenous factors have long been identified as modifiers of the natural history of HPV infections leading to cervical cancer. Many of the early caseecontrol studies were conducted in populations with low coverage of screening for cervical cancer. Most relevant cofactors identified at the time to increase cervical cancer risk were long-term smoking, multiparity [68], and long-term use of hormonal [69] contraceptives with an average increased risk of 1.5e2-fold in HPV-positive women [70]. Interestingly, a recent analysis of a large cohort of 308,036 Fig. 5. Most common HPV types detected in HPV DNA positive anogenital invasive cancer in the RISHPV studies. S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 10 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study, with an average follow-up of 9 years, confirmed that increasing number of full-term pregnancies was positively associated with increased risk of cervical intraepithelial neoplasia grade 3/carcinoma in situ (CIN3/CIS) and that duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and cervical cancer with hazard ratios of 1.6 and 1.8, respectively, for 15 years versus never used [71]. Identification of persistent HPV infection in smokers should alert women of the increased risk and reinforce the message to quit smoking. In HPV-positive long-term oral contraceptive users, a closer surveillance for cervical disease may be advisable. Coinfection with sexually transmitted infections with Chlamydia trachomatis has been inconsistently associated with the risk of progression to cancer. A prospective study exploring the association between C. trachomatis DNA and C. trachomatis immunoglobulin G status among HPV-positive women and the risk of preneoplastic lesions did not find any association. The authors suggested that previous positive associations may be explained by a confounding effect of HPV acquisition [72]. In a recent meta-analysis [73], Zhu H et al. reported a significant increase of cervical cancer incidence in both retrospective and prospective studies associated to C. trachomatis. The increased risk was observed even after adjustment for HPV detection. The authors suggest that an independent effect could be attributed to C. trachomatis. Consistency in prospective studies is still needed to confirm such a role of C. trachomatis as coinfection may be affected by the sexual pathway that both infections share. HIV has always been associated as a major co-factor with HPV to induce cervical cancer. The mechanism has been largely associated to the immunosuppression conferred by active HIV infection and not by a direct effect of HIV. A large number of HIV-infected women are now following antiretroviral therapy (ART), and therefore, it is expected that a good compliance with treatment will be followed by a reduction of cervical lesions and cervical cancer [74]. A recent analysis compiling the existing literature shows that women complying with ART in a prolonged time lower their risk of acquisition of high-risk HPV types and lower the incidence of intraepithelial lesions and their progression [75]. In some settings, like in Eastern and South Africa, the high prevalence of HIV infection in women alerts of the need to fully control ART compliance to prevent additional damage due to HPV infection and its consequences. Further details on the impact of HIV in HPV-related disease are shown in a following chapter 8. Conclusion Many enigmas, however, remain to fully understand the natural history of HPV and related diseases. Some HPV types and particularly HPV16 have an enormous capacity to induce cancer in humans through clearly identified oncogenes, E6 and E7. The cervix uteri is the tissue that is most vulnerable to these HPV infections if they persist. In addition to viral load and viral type, factors such as smoking, hormonal use, and coinfections with HIV may contribute to the progression of HPV infections into human cancer. Prevention by vaccination and/or screening and improved treatment are key to reduce the burden of HPV-related disease. Financial support This work was partially supported by grants from the Instituto de Salud Carlos III-ISCIII (Spanish Government) co-funded by FEDER funds/European Regional Development Fund (ERDF) e A WAY TO n cooperativa en salud (RETICS) BUILD Europe (References: PI16/01254; Redes tem aticas de investigacio n me dica en Red: CIBERESP CB06/02/0073 and CIBERONC: RD12/0036/0056, Centro de Investigacio n de Ayudas Universitarias y de Investigacio n (AGAUR) de la GenCB16/12/00401), Agencia de Gestio eralitat de Catalunya (2014SGR756) and Recercaixa 2015 (MD088652). The work conducted by M. Brotons was supported by a grant from the Spanish Ministry of Economy and Competitiveness e Carlos III Institute of Health (Río Hortega CM15/00061). Conflict of interest SdS holds an Institutional Research Grant from Merck. S. de Sanjose et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 47 (2018) 2e13 11 Practice points Prevalent HPV infection may represent a long-standing infection. 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