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Journal of Bacteriology and Virology 2015. Vol. 45, No. 3 p.179 – 188 http://dx.doi.org/10.4167/jbv.2015.45.3.179 Review Article

Influence of the Host Factors on Human Papillomavirus and Efficacy

* Sung-Hwa Sohn and Jae-Hwan Nam

Department of Biotechnology, The Catholic University of Korea, Gyeonggi-do, Korea

Human papillomavirus (HPV) is associated with cervical cell changes, genital warts, recurrent respiratory papillomatosis, laryngeal papillomatosis, head and neck , and cervical cancer. Two commercial HPV have successfully been made available in the clinical field. This review covers the progress of cervical disease by understanding the nature of HPV infection, as well as the relationship between the host factors and HPV vaccine effectiveness. Among these host factors, microbiota has been revealed to influence the development and function of both the innate and adaptive immune systems. Therefore, the composition of the microbiome may ultimately affect vaccine efficacy. Understating the relationship between host factors and HPV infection/vaccine efficacy may prove to be useful in earlier diagnosis, as well as disease prophylaxis. Key Words: HPV, Vaccine efficacy, Probiotics, Microbiota

sequent development of cervical have been exten- INTRODUCTION sively studied, there are many unknowns in the relationship between the host factors (e.g. genetic polymorphism, micro- Humans are constantly exposed to pathogenic micro- biome, disease status, and immune system) and HPV vaccine organisms, including viruses, bacteria, and fungi. Among effectiveness. Among the various host factors affecting these , human papillomavirus (HPV) is the vaccine efficacy, the role of the microbiome has now been most common sexually transmitted infection worldwide (1). established (4, 5). In this review, we will summarize the Currently, two HPV commercial vaccines have been recent data on the relationship between the host factors, approved for use in the clinical field. These are termed especially microbiota composition, and both HPV vaccine '' and '', which cover 4 (6, 11, 16 and 18) efficacy and HPV infection. and 2 (16 and 18) HPV types, respectively (2). In December 2014, Gardasil 9 was approved in the USA, which covers 9 Basics of HPV infection HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58) (3). The characters of these HPV vaccines are summarized in Table HPV is a circular double-stranded DNA (dsDNA) virus 1. While the mechanism of HPV infection and the sub- for which more than 200 different types have been identified

Received: May 30, 2015/ Revised: June 10, 2015/ Accepted: June 25, 2015 *Corresponding author: Jae-Hwan Nam, Ph.D. Department of Biotechnology, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, 420-743, Korea. Phone: +82-2-2164-4852, Fax: +82-2-2164-4917, e-mail: [email protected] **This study was supported by a grant from the Korean Healthcare Technology R&D project of the Ministry of Health & Welfare (A103001 and HI13C0826), and by a grant from Gyunggi Regional Research Center (GRRC) of the Catholic University of Korea.

○CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/license/by-nc/3.0/).

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Table 1. Characteristics of anti-HPV vaccines

Bivalent vaccine Quadrivalent vaccine Ninevalent vaccine Commercial name Cervarix® Gardasil® Gardasil® 9 HPV 6/ 11/ 16/ 18/ 31/ 33/ HPV types HPV 16/ 18 HPV 6/ 11/ 16/ 18 45/ 52/ 58 Trichoplusia ni (Hi 5) insect Saccharomyces cerevisiae Saccharomyces cerevisiae Producer cells cell line infected with L1 expressing L1 expressing L1 recombinant baculovirus Girls and women: 9~26 years: Administration Girls and women: 9~14 years: Girls and women: 9~13 years: 0, 2, 6 months schedule 0, 1, 6 months 0, 2, 6 months Boys: 9~15 years: 0, 2, 6 months Aluminum hydroxide and Aluminum hydroxyphosphate Aluminum hydroxyphosphate Adjuvant 3-O-deacylated-4-monophosphoryl sulfate sulfate or AAHS lipid A

and categorized into high- and low risk (6). HPV has a non- (L1 and L2) and three oncoproteins (E5, E6 and E7) (17, enveloped, icosahedral capsid, and infects only mucosal or 18). The major capsid L1 self-assembles into virus- cutaneous epithelium (7). The fifteen types of HPV classified like particles (VLPs), which are in tertiary or native form as high risk include HPV16, 18, 31, 33, 35, 39, 45, 51, 52, and are assembled as multimers to generate neutralizing 56, 58, 59, 68, 73, and 82 (8). In particular, HPV 16 and 18 antibodies. HPV L1 VLP vaccines have been developed are known to cause up to 70% of cervical cancers (9). The commercially (Table 1). VLP vaccines are highly immuno- low risk HPV types include types 6, 11, 42, 43, and 44, genic and induce HPV neutralizing antibodies, which persist which are involved in the development of cervical cell for at least 5 years after . The HPV E5 protein changes, genital warts, recurrent respiratory papillomatosis, suppresses the expression of MHC class I and antigen and laryngeal papillomatosis (10~12). processing via the transporter associated with the antigen Cervical cancer, the second most prevalent cancer among processing pathway (19, 20). HPV E6 ubiquitinates (ubi- women, is associated with HPV infection (13). To detect quitin mediated degradation) the p53 tumor suppressor potentially dangerous HPV strains and to defend against protein (21), whereas E7 ubiquitinates the retinoblastoma infection, humans have developed effective innate and (pRb) tumor suppressor protein (22), indicating that these adaptive immune systems that minimize the impact of two may have oncogenic effects. In addition, the pathogens on human health. On the other hand, HPV uses HPV E6 protein causes downregulation of the expression specific life strategies to enable its survival and persistence of interferon-related and transcription factor NF-κB within the epithelial cells, including diverse mechanisms to (23). NF-κB activates a local immune response (e.g., MHC evade host immune surveillance via programming for natural class I, interleukins and GM-CSF) and an IFN-β promoter cell death, which causes the progeny virions only to be (24). Inhibition of NF-κB may help the HPV virus to escape released in high quantities from terminally differentiated immune recognition. The HPV E7 protein blocks cell cycle epithelial cells (14). HPV infects only mucosal or cutaneous regulatory genes are required for G1/S transition and DNA epithelium. In addition, HPV induces a slow and weak replication. These proteins (E5, E6 and E7) are also able to immune response, which inhibits interferon synthesis (15, break antigen presentation (25) (Fig. 1). Therefore, these 16). three proteins also play roles in the evasion of the innate The HPV genome encodes two structural capsid proteins and adaptive immune system, which creates a favorable

Host Factor Ramifications on 181

Figure 1. A schematic diagram of a possible mode of the oncogenic action of human papillomavirus (HPV). HPV infection into a host tissue leads to oncogenic processes. HPV E5 protein suppresses the expression of MHC class I and antigen processing. HPV E6 protein binds p53 tumor suppressor protein and this binding blocks p53 defense mechanisms, as well as p53-induced antiviral activity (down-regulates the expression of the antiviral interferon-related genes and the transcription factor NF-κB), through cell cycle arrest and apoptosis of the infected cell by degradation of p53 via ubiquitination. HPV E7 protein binds pRb cell cycle regulatory protein, which can block cell cycle arrest by degradation of Rb via ubiquitination. Therefore, these proteins play roles in tumor promotion. These HPV E5, E6, and E7 proteins are able to impair the innate and acquired immune response, which play roles in the evasion of the host immune system. MHC class I, major histcompatibility complex class I; pRb, retinoblastoma protein; Ag, antigen; IFN, interferon gamma; NF-κB, nuclear factor-κB.

environment for viral replication (26). It is thought that E6 1. Impact of host genetic factors on HPV infection and E7, from the low risk HPV types, may have weaker binding to their target proteins compared to the high risk Population based association studies (genetic polymor- types (27). phisms) often estimate the risk of developing a certain disease in carriers and noncarriers of a particular genetic Factors affecting HPV infection and vaccine polymorphism (30). The population genetic background contributes to the susceptibility to developing cervical cancer Many factors affect HPV infection, including sex, estrogen after HPV infection. The p53 Pro/p53 Arg polymorphism hormones, microbiome, genetics, epigenetic phenomena, age, should influence the outcome of HPV infection, because nutrition, immune system, and infectious and autoimmune the presence of heterozygous p53 Pro is more resistant than diseases (28, 29). p53 Arg to E6-mediated degradation. Those with the p53 Arg allele, in the absence of the p53 Pro allele, are there- fore at increased risk of developing cervical cancer (31).

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Moreover, polymorphism in the proinflammatory cytokine 3. Impact of host immune factor on intestinal micro- Tumor necrosis factor-α (TNF-α) also causes increased biota the risk of HPV associated cervical cancer in the presence of HPV. TNF-α-308 G/A polymorphism may play a role in Recognition of microorganisms by the innate immune TNF-α production and the inflammatory response during system involves pattern recognition receptors (PRRs), such the course of cervical cancer. In particular, the A allele is as nucleotide binding oligomerization domain (Nod) like associated with an increased risk of invasive cervical cancer receptors (NLRs) and Toll like receptors (TLRs), which dis- (32, 33). Individuals with the TNF-α-308 G/A and -238 criminate pathogen associated molecular patterns (PAMPs) G/A promoter genotypes are at increased risk of developing or danger associated molecular patterns (DAMPs) (52~54). inflammatory, infectious and (33). Extracellular contaminants are recognized by TLRs, whereas These results suggest that host genetic polymorphisms can surveillance of the cytoplasm is the work of NLRs, recog- influence the nature and extent of HPV-mediated disease. nized by their Nods (52, 55). Among the various TLRs, TLR4 recognizes pathogen bacterial LPS, but is not stimu- 2. Impact of host microbiome on metabolic disorder lated by commensal microflora, which have detoxified forms and chronic inflammatory disease of LPS, dephosphorylated by an intestine-specific isoform The interplay between HPV, the gut epithelium, and host of alkaline phosphatase (36). TLR5 recognizes bacterial innate defense responses is among the most critical factors flagella, and its signaling can stimulate CD11bhighCD11chigh determining the fate of HPV and disease out- DCs to express Raldh2, which catalyzes the conversion of comes. Recently, gut microbiota were found to contribute vitamin A to retinoic acid. Retinoic acid can then cause B to many host physiological processes and disease (34, 35). cells to differentiate into IgA producing plasma cells (56). Theses intestinal microbiota make important contributions Secreted IgA is required for keeping commensal bacteria to the health of their hosts by protect against pathogens via that can determine the nature of bacteria. IgA regulates the appropriate development of the immune system and syn- ecological balance of microbiota, which regulates the com- thesis of essential vitamins (35, 36). It should also be noted position and character of microbiota. IgA protects against that these essential vitamins, such as vitamin A and D, are viruses from the epithelium by binding, rather than cellular also important for immune function and vaccine effectiveness neutralization. Furthermore, IgA, an adaptive response effector, (37). In addition, there is an abundance of NK, Th17 and is crucial for the compartmentalization of the microbiota to Treg cells in the intestinal mucosa, and their accumulation the intestinal lumen (57) (Fig. 2). However, Tlr5-/- mice and function are affected by the presence of the microbiota exhibit similar changes in the microbiota shape as ob/ob (38). Infant gut microbiota has a relatively simple com- mice (leptin gene deficiency). The Tlr5-/- phenotype is due position, which is affected in large part by the maternal to changes in the microbiota, causing hyperphagia and microbiota due to the delivery method, such as cesarean or metabolic syndromes, including insulin resistance, hyper- vaginal birth (39). Moreover, community and function of lipidemia, and obesity (43). TLR9 recognizes the viral or the microbiota can change owing to numerous variables, bacterial dsDNA derived CpG motifs, but its transcription including lifestyle, diet, hygiene, and use of antibiotics (40). is inhibited by recombinant HPV 16 E6 and E7 (26). Two of the main types of intestinal microbes, the Fir- TLR2 and Nod2 are both required for the transcriptional micutes and Bacteroidetes, have also been linked to obesity induction of pro IL-1β and the priming of the , and metabolic disorders (41~43). Furthermore, microbiota which is mediated by the upregulation of NLRP3 (58). composition is also related to incidence of chronic inflam- Inflammasome activation is thought to require two signals, matory diseases, such as allergic conditions, chronic colitis, the first involving the sensing of conserved PAMPs which and autoimmune disorders (44~51). induce expression of certain inflammasome components and

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Figure 2. A schematic diagram of possible mode for the relationship between the microbiota and the immune system in the intestinal lamina propria. The microbiota is composed of a variety of bacteria with different characters. The microbiota influence the development and function of both the innate and adaptive immune systems. The intestinal microflora has TLR5 ligans such as flagellin. TLR5 signaling stimulates CD11bhighCD11chigh DCs, which can catalyze the conversion of vitamin A to retinoic acid; this causes B cells to differentiate into IgA producing plasma cells. Secreted IgA regulates the ecological balance of microbiota, which regulates the composition and character of microbiota. Ultimately, IgA induces compartmentalization of the microbiota to the intestinal lumen, and it contributes to protection from viral infections. HPV, human papillomavirus; TLR5, toll like receptor 5; DC, dendritic cell; IgA, immunoglobulin A; Raldh2, retinaldehyde dehydrogenase 2.

cytokines, and the second involving disruption of cellular bacteria that have proinflammatory activities (46, 62, 63). membranes or signaling pathways (59). Cytosolic dsDNA Nod2-/- mice are susceptible to pathogen infection because from intracellular pathogens such as HPV is sensed by of an intrinsic defect in their ability to kill the bacteria. In AIM2, which triggers formation of the inflammasome com- addition, these mice also have increased populations of plex with ASC to activate 1-mediated processing commensal bacteria in the intestine, suggesting that NOD2 of IL-1β and IL-18 (60, 61). Recent studies have suggested plays a crucial role in regulating between that inflammasome deficiency may be associated with bacterial flora and innate immunity (64). Moreover, NLRP6 stimulator-induced inflammation, inducing tumorigenesis deficient mice exhibited increased members of Prevotell- in the intestine and chemical colitis, due to alterations in aceae and TM7, and reduced members of Lactobacillus, the microbiota and the emergence of normally suppressed which caused increased intestinal inflammatory cell recruit-

184 S-H Sohn and J-H Nam ment and susceptibility to chemically induced colitis. These malnutrition, or hygiene (66), which may easily affect the mice phenotypes resembled ASC-/- mice (46). Therefore, microbiota composition. Consequently, based on these well- host immune factors may drive disease-specific alterations in founded conjectures, microbiota may affect vaccine responses the microbiota, which in turn may promote the development indirectly or directly through action on various immune of disease in the host. responses, such as development of CD4+ T cells (67). Immunization is necessary to prevent morbidity and mor- 4. Impact of host microbiome on HPV vaccine efficacy tality from infectious diseases, such as HPV. Actually, the The human intestinal tract harbors a large number of main goal of vaccination is to elicit memory B cell responses species which intimately interact with nutrition status, gen- and CD4+ T cell-mediated neutralizing immune effector etics, metabolism, and the immune system (65). The micro- responses. B cell memory response to antigen recall is an biota ultimately contribute to host physiology via fostering important factor for the long-term efficacy of vaccine- normal development of the immune system and influencing induced humoral protection. The protection achieved by the ensuing immune responses. Interestingly, vaccines often HPV vaccines against incident HPV infection and HPV- have lower effectiveness than expected when used in associated pathology is mediated via serum neutralizing developing countries, possibly due to intestinal dysbiosis, IgG (68). By the way, recent studies have shown a trend

Table 2. Summary of the impact of probiotics on vaccine efficacy

Probiotics Vaccines Biological effects Lacrobacillus casei D x RRV rhesus-human LGG has an immunostimulatinq effect on rotavirus vaccination strain GG (LGG) reassortant via enhance IgA production and release of interferon γ. LGG stimulated IgA sASC responses against S. typhi Ty21a. LGG or Lactococcus lactis Salmonella typhi L. lactis has increase CR3 receptor expression on the neutrophils (L. lactis) Ty21a vaccine which can influence the non-specific immune response. LGG and Bifidobacterium lactis LGG and BB12 acted as an immunostimulant for AttHRV AttHRV vaccine BB12 (BB12) vaccine via modulated DC activation and responses. L. lactis, Lactobacillus plantarum These bacteria have induction of Th1 response in eczema and Allergy vaccines or Bifidobacterium bifidum asthma models. Mycobacterium vaccae Heat-killed M. vaccae induces Treg cells and decreases airway Allergy vaccines (M. vaccae) inflammation in or asthma murine model. Bifidobacterium breve strain A trend towards increased serum IgG after administration of Yakult (BBG-01) BBG-01 Bifidobacterium longum BL999 BL999 and LPR were improved HepB surface antibody (BL999) and Lactobacillus B vaccine responses in subjects. rhamnosus LPR (LPR) Lactobacillus paracasei ssp. Diphtheria, tetanus and LF19 was increased the capacity to raise immune responses in F19 (LF19) Hib vaccines infants breastfed < 6 months. Live attenuated influenza LGG LGG was increased protective hemagglutinin inhibition titers. vaccines L. fermentum A trend towards increased TNF-α, total IgG and IgM, and Inactivated CECT5716 (LCECT5716) influenza-specific IgA after administration of LCECT5716. BB12 and L. paracasei BB12 and L431 were elevated influenza specific IgG levels and Inactivated influenza vaccine 431 (L431) influenza specific IgA responses.

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