Role of human papillomavirus and associated viruses in bladder cancer: An updated review

Bladder cancer (BC) is a complex disease affecting the urinary system and is regulated by several carcinogenic factors. Viral infection is one such factor that has attracted extensive attention in BC. Human papillomavirus (HPV) is the most common sexually transmitted infection, and although multiple researchers have explored the role of HPV in BC, a consensus has not yet been reached. In addition, HPV‐associated viruses (e.g., human immunodeficiency virus, herpes simplex virus, BK virus, and JC virus) appear to be responsible for the occurrence and progression of BC. This study systematically reviews the relationship between HPV‐associated viruses and BC to elucidate the role of these viruses in the onset and progression of BC. In addition, the study aims to provide a greater insight into the biology of HPV‐associated viruses, and assess potential strategies for treating virus‐induced BC. The study additionally focuses on the rapid development of oncolytic viruses that provide a potentially novel option for the treatment of BC.


| INTRODUCTION
Bladder cancer (BC) is the tenth most common cancer worldwide, 1 with an estimated 550 000 new occurring cases annually. 2The incidence of BC demonstrates significant geographical disparities, with a higher prevalence in developed areas (e.g., Europe, North America, and parts of Western Asia) than in developing areas (e.g., Africa and South Asia). 3The global prevalence of BC in women is lower than that of men (about a quarter of the incidence rate of men), with significant sex-based differences among countries. 4In addition, the lifetime treatment of BC is considerably expensive, costing approximately 400 million euros annually in the United States and nearly 600 million euros in Europe, imposing extensive financial burdens on individuals and society. 5,6Histologically, BC is classified into urothelial carcinoma (UC), squamous-cell carcinoma (SCC), and adenocarcinoma, 7 with UC accounting for approximately 95% of all subtypes, including differentiated and histologic subtypes. 2Based on whether the tumor invades the muscle layer, BC can be further classified into muscle-infiltrating BC (MIBC) and non-muscleinfiltrating BC (NMIBC). 8Approximately 75% of patients present with NMIBC, which is characterized by cancer development in the bladder mucosa or submucosa.Clinically, local resection and bladder perfusion are usually employed for this stage. 9,10In contrast, MIBC penetrates into the muscle layer and is often treated using transurethral resection of bladder tumors, radical cystectomy, combined chemotherapy or radiotherapy or palliative therapy. 11,12oking continues to be a crucial, independent risk factor for the development of BC.Studies have found that individuals with a persistent smoking habit are at a three times higher risk of developing BC than non-smokers. 13,14Schistosomiasis is another notable etiological factor of SCC that is predominantly prevalent in the Egyptian population. 159][20] The International Agency for Research on Cancer (IARC) has indicated that infections are the primary etiological factor of cancer, contributing to approximately 15% of new cancer diagnoses annually.Specifically, viral infections alone are responsible for 10% of all cancer diagnoses, of which 4.5% are caused by HPV infections. 21In addition, the IARC report defines viruses including hepatitis B virus (HBV), hepatitis C virus (HCV), HPV, and human immunodeficiency virus (HIV) as Group I "carcinogenic to humans." 20Undoubtedly, the development of cancer is a multifaceted and complex process, in which viral infection takes a critical role in carcinogenesis.Urothelium is the waterproof membrane that stretches from the renal pelvis to the bladder and protects the urinary tract from infections.Moreover, the structure undergoes rapid shedding and regeneration cycles following acute injury or infection. 22,23The urothelium is also the site from where BC originates, with persistent infection and chronic inflammation leading to permanent alteration of the urothelial structure that accelerates cancer development. 24Given the anatomical proximity of the urinary tract to the genital tract, it is reasonable to hypothesize that virus may spread upward through the urethra to the bladder epithelium, causing the development and progression of BC (Figure 1). 25,26 addition to HPV, several HPV-associated viruses such as HIV, herpes simplex virus (HSV), BK virus (BKV), and JC virus (JCV) have been linked with BC (Table 1). 19,20,27Reportedly, infection with one virus tends to induce co-infection with other viruses, which persist in the body for a long time and trigger associated symptoms due to suppressed immunity. 19However, the studies conducted across different regions provide contradictory results.
Accordingly, this study aimed to comprehensively reviewed the new data on the role of HPV and related viruses in the occurrence, development, and prognosis of BC.The findings will help provide a better understanding of the correlation between HPV-associated viruses and cancer pathogenesis, as well as determine valuable strategies for treating virus-induced BC.

| HPV AND BC
HPV is a family of circular DNA viruses that infect mucous membranes and skin epithelium and is the causative factor for most sexually transmitted infections. 18,28HPV primarily occurs via skin-to-skin contact as well as through nonsexual contaminants, such as prolonged exposure to shared contaminated clothing. 29In the United States alone, the prevalence of genital HPV infection in males aged 18-59 years is 45.2%. 302][33] The evolutionary branch of HPV consists of five components, including α, β, γ, mu, and nu, with the α subtype infecting mucosal tissue and the other subtypes affecting skin tissues. 34E6 and E7 are two pivotal oncoproteins of HPV that The oncogenic process of human papillomavirus (HPV) and related viruses in the bladder.After the attack of the virus on bladder uroepithelial cells, DNA repair ensures that damaged cells attain normal conditions.Cells that fail to repair transform into pre-cancer cells after persistent chronic infection.Accompanied by genomic changes and the absence of tumor suppressors, these pre-cancer cells gradually develop into cancer cells.promote tumorigenesis by inducing the degradation of tumor suppressors p53 and Rb as well as disrupting cell cycle regulation and DNA repair pathways. 35In vitro studies have shown that E6 binds to p53, leading to rapid protein breakdown via the ubiquitin pathway, and this activates Cdk-cyclin and cellular recycling. 36E6 proteins encoded by high-oncogenic HPV (HPV16, 18) appear to have a stronger binding affinity for p53 and/or considerably accelerate the degradation of p53 compared with E6 proteins of the low-oncogenic HPV. 37Moreover, the HPV E7 protein combines with cell cycle-associated proteins, including Rb and p107, to participate in cellular transformation.The ultimate outcome of E7-Rb binding is the liberation of the E2F transcription factor complex by Rb, which accelerates the transcription of proliferation-dependent genes (Figure 2). 36In addition, based on its carcinogenic potential, HPV can be classified into low-risk and high-risk groups.Low-risk HPVs, such as 6, 11, 42, 43, and 44, are responsible for approximately 90% of anogenital warts; however, these strains rarely cause cancer.Conversely, high-risk HPVs, such as 16, 18, 31, 33, and 34 are associated with approximately 90% of cervical cancers, most anal cancers, and vulvar and penile cancers. 18,38,39cently, extensive evidence has demonstrated a strong correlation between HPV and BC, with the virus significantly affecting the development and prognosis of BC (Table 2). 40In their study, Sun et al. 41 reported that HPV infection was correlated with a significantly increased risk and a worse prognosis for BC.Moreover, HPV infection causes chronic inflammation, which induces the excessive release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from epithelial cells, leading to DNA damage.Accumulated damage accelerates DNA mutations, ultimately fostering the initiation and progression of carcinogenesis. 42Several studies have assessed the effect of HPV infection on the bladder epithelium owing to the anatomical proximity of the bladder and genital organs and sexual transmission. 26,41Moreover, HPV DNA has been detected in urine and washing specimens of patients with BC as well as in BC tissues. 43,44In addition, high-risk HPV infection is positively correlated with tumor progression, which was attributed to p53 mutation. 45,46Evidence has also suggested the presence of lowrisk HPVs in BC tissues; however, these viruses may not induce carcinogenesis. 47e susceptibility of BC to HPV infection may differ with histological types, and this controversy has been mainly associated with UC and SCC.In retrospective studies from the United States, HPV was not detected in primary SCC 48,49 ; however, the signal amplification invader assay identified the presence of high-risk HPV DNA in a minority of patients. 49Another multicenter retrospective study of 207 cases found that although SCC expressed p16 (a surrogate markers of HPV infection), it was not associated with highrisk HPVs and may be present in medical curiosity. 50Interestingly, multiple studies globally have identified a remarkable positive association of UC with HPV infection, particularly infection with high-risk HPVs, [51][52][53][54][55][56] highlighting the role of HPV in the etiology and T A B L E 1 Characteristics of five HPV-associated viruses.progression of UC. 27,57 Moreover, high-risk HPV infection is predominantly prevalent among young women with a history of cervical cancer in UC, thereby serving as a discriminant between primary cervical cancer and UC. 58,59A recent Chinese study has demonstrated that although the protein E6 promotes the development of UC, there exists a positive correlation between high E6 expression and favorable prognosis.This may be attributed to E6

Virus
promoting the upregulation of APOBEC3B, a member of the Apolipoprotein B mRNA-editing enzyme catalytic polypeptide as well as exerting an antiviral role by inducing cytidine deaminase activity. 60In addition, UC is usually accompanied by focal squamous differentiation, forming BC with squamous differentiation (BC/SCC) that includes epithelial and squamous phenotypes. 61Specifically, HPV is also associated with UC with squamous cell differentiation, which contributes to poor prognosis. 40,62portedly, differences were observed in HPV infection within the same histological types.Unlike the aforementioned research from the United States, 48,49 study from Denmark indicated that approximately one-fifth of SCC cases were associated with HPV infection, 63 whereas another study detected multiple HPV subtypes in female patients. 64Similar findings were noted for UC.Georgios et al. 65 demonstrated that HPV DNA was undetectable in UC samples, providing compelling evidence against the association of HPV and the Greek population.Another study in British patients with UC similarly failed to support the existence of HPV DNA sequences in cancer samples. 66In addition, Khatami et al. 67 revealed no remarkable association between HPV infection and BC.9][70] Currently, it is unclear why the association between HPV infection and UC differs with geography; however, these may be ascribed to genetic variations and racial disparities, as Asian and European BC patients exhibit a higher susceptibility to HPV infection. 47though the relationship between HPV infection and the etiology and progression of BC remains unclear, the present systematic review of the extensive literature shows that these differences in the association between HPV and BC may not apply to tissue subtypes.Most studies have suggested a positive association between HPV (especially high-risk HPV) infection and BC (particularly UC), although a few studies have considered that HPV may not be a causative factor.These inconsistent findings may be based on geographic and ethnic cultures, as the route of HPV infection is mainly transmitted via sexual contact.
As HPV infection was associated with SCC in only a limited number of independent studies, the odds of publication bias could not be determined.Furthermore, only one study suggested that UC/SCC was associated with HPV infection.Consequently, multicenter and large-scale studies are required to clarify this association.
The potential mechanism of virus-induced tumorigenesis in human papillomavirus (HPV), BK virus (BKV), and JC virus (JCV).HPV disrupts the regulation of the cell cycle after infection in two ways.One is via the binding of E6 oncoprotein to P53, which leads to proteolysis via the ubiquitination pathway, thereby activating the cdk cycle and the cell cycle.The other is by the binding of E7 oncoprotein to Rb and other related proteins, which releases the E2F transcription factor complex and activates the cell cycle.The T Ag of BKV and JCV binds to Rb and releases E2F, forcing cells to enter the S stage.In addition, the C-terminal domain of T Ag interacts with p53 and inhibits cell apoptosis, resulting in uncontrolled cell growth.Cdk-cycle, Cyclin-dependent kinase cycle.
T A B L E Characteristics of studies on the role of HPV in BC.HIV is a single-stranded RNA virus that cause a high-risk, infectious disorder known as acquired immune deficiency syndrome (AIDS), which can broadly be classified into HIV-1 and HIV-2. 71Currently, more than 38 million people worldwide are presently infected with HIV, with approximately one million new infections and 600 000 deaths occurring annually. 72The primary modes via which HIV spreads are sexual behavior, blood transfusion, and vertical transmission. 73Following infection, HIV impairs immune function via the destruction of crucial CD4 + T lymphocytes, which predisposes individuals to a malignant disease with high mortality. 74,75Previous views suggested that HIV causes progressive loss of CD4 + T cells and immune abnormalities through viral cytopathic effects (i.e., the virus replicates extensively in susceptible cells and ultimately induces cell death). 76However, the low frequency of these activated CD4 + T cells does not seem to support the significant loss of CD4 T cells observed in vivo. 77Therefore, researchers further explored and found that most cells do not die due to the toxic effects of HIV, but as a result of the strong defensive immune response produced by host cells against viral infection. 78Specifically, if the virus infects activated cells (5% of CD4 T cells), it activates of caspase-3 mediates cell apoptosis.On the contrary, if the virus infects cells in resting state (95% of CD4 T cells), caspase-1 is activated and triggers cell pyroptosis (Figure 3A). 79This may also be the underlying cause of chronic inflammation in HIV patients.Antiretroviral therapy (ART) is a crucial intervention in the global fight against HIV infection as it effectively impedes the progression of AIDS.Nevertheless, limited healthcare resources in low-and middle-income countries pose significant challenges in managing HIV infection. 80dividuals with HIV infection are generally at an increased risk for BC owing to high rates of smoking, which is an independent hazard factor for BC.However, studies investigating the relationship between CD4 count and BC incidence at the time of AIDS have revealed a notably lower risk of BC in patients with AIDS than in those without AIDS. 81Additionally, an assessment of the clinical characteristics of HIV-associated BC has revealed that HIV-positive patients are typically younger and exhibit signs of immunosuppression. 82,83Moreover, the largest single-center study conducted in France showed that the prevalence of BC in patients with HIV infection was only 0.2%, and its overall prevalence was significantly lower in patients with BC than in those with other malignancies. 84Notably, the cohort in this study was predominantly male, with nearly two-thirds reporting a habit of smoking, and most were receiving combination ART.Moreover, histopathology analysis revealed that 80% of the patients had UC, with a significant proportion of patients demonstrating muscle invasion (47%) and a high histological grade (73%).These findings suggest that BC in patients with HIV infection is characterized by aggressive behavior and poor prognosis.Most importantly, the prognosis of BC patients with HIV infection appears to be indistinguishable from those without HIV infection. 84Thus, it is recommended that such patients be managed according to the BC treatment guidelines for HIVnegative individuals. 10I G U R E 3 The potential mechanism of virus-induced tumorigenesis in human immunodeficiency virus (HIV) and herpes simplex virus (HSV).
(A) HIV impairs the immune function by destroying key CD4 + T lymphocytes through cell apoptosis and pyroptosis.(B).HSV interferes with immune signal transmission through the interaction of envelope glycoproteins with surface receptors of dendritic cells (DC).In addition, HSV causes damage to the DC cell membrane, leading to abnormal immune signal release and virus spread.
HSV is a double-stranded, enveloped DNA virus of the genus Herpesvirus.HSV can be classified into serotypes: herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), which are associated with a global prevalence of approximately 67% and 13%, respectively. 85,86e virus is transmitted through intimate contact and results in a lifelong infection.HSV-1 typically spreads via the oral mucosa and during the initial stages of the infection, whereas HSV-2 is commonly transmitted sexually and in the later stages of infection.Usually, infection with either type of HSV triggers an immunological memory, which prevents reinfection with the same type; however, this does not provide cross-protection against the type of HSV. 87As an envelope virus, HSV interferes with immune signal transmission through the interaction of various typical envelope glycoproteins (gB, gC, gD, gH/gL) with surface receptors of DC cells (the main antigenpresenting cells), 88,89 disrupting innate immunity and promoting T cell-mediated adaptive immune abnormalities. 90In addition, HSV causes damage to the DC cell membrane, leading to abnormal immune signal release and virus spread.This event inevitably accelerates the infection of other cells and may trigger abnormal immune signals in multiple immune cells, resulting in various inflammatory and tumor diseases (Figure 3B). 91,92Indeed, due to the interaction between different surface glycoproteins and cell receptors involved in HSV infection, it means that blocking virus infection requires a combination of multiple neutralizing antibodies. 92,93HSV has evolved various strategies to evade the innate immunity, 94 owing to which effective methods or vaccines for treating patients have not yet been developed.Consequently, the prevention and control of HSV virus transmission remain extremely challenging. 95,96eviously, HSV was considered as a cofactor in the pathogenesis of human malignancies.In a cross-sectional study assessing biopsy specimens of 16 patients with BC, HSV gene sequences were identified in 9% of all tissue specimens, guiding the stage for subsequent exploration of the relationship between HSV and BC. 97tably, HSV-1 and HSV-2 are broadly recognized to induce chronic and latent infections in the genitourinary tract, leading to cellular atrophy as well as pathological changes in the intranuclear inclusion bodies. 98In addition, HPV has been found to potentially trigger HSV infection 99 ; moreover, both HSV and HPV have been detected in BC samples using polymerase chain reaction (PCR) in a study of BC. 65,100 Therefore, the potential contribution of HSV infection in the development of BC cannot be ignored.

| BKV AND BC
BKV (family: polyomavirus) is a single-stranded, envelope-free RNA virus with a genome size of approximately 8.3 kb.It consists of a genome with 5′ and 3′ non-coding regions, and an open reading frame encoding a multiprotein precursor that comprises three functional protein-coding regions (P1, P2, and P3). 101According to the hypervariable region of the capsid protein VP1, BKV has been classified into four genotypes.BKV genotype I is the most popular worldwide (incidence: approximately 80%), followed by genotype IV (approximately 15%), which is mainly prevalent in Europe and East Asia.Genotypes II and III accounting for approximately 5% of all cases, and are found in all geographic regions. 102,103In the United States, the prevalence of BKV antibody seropositivity among adults ranges from 63% to 81%. 104The initial BKV infection is usually acquired in childhood, with seropositivity ranging from approximately 50% in children aged 3-4 years to 91% those aged 5-9 years. 105,106V is prevalent globally and is also considered a risk factor for BC. 107,108Primary infection is typically asymptomatic, 109 despite nonspecific upper respiratory symptoms are present in certain populations. 110Following initial infection, BKV remains latent within the urothelium and reactivates during periods of immunosuppression to establish persistent infection, resulting in BKV-associated nephropathy after kidney transplantation as well as hemorrhagic cystitis. 100,111,112Moreover, BKV encodes a nonstructural protein, the large tumor antigen (T Ag), which binds to and inactivates the oncogenic proteins p53 and pRb.This leads to abnormal cell cycle, immortalization of cellular, and tumorigenesis (Figure 2). 113,114eviously, researchers generally believed that BKV was not associated with the development of BC, as T antibody-positive sera did not significantly differ between patients with cancer and normal controls.Moreover, the application of another gene probe technique for detecting BKV failed to demonstrate the involvement of the virus in the pathogenesis of BC. [115][116][117] In addition, a comprehensive case series of 76 BC tissues detected BKV DNA and T Ag, using quantitative real-time fluorescent PCR (qRT-PCR) and immunohistochemistry, respectively.This suggested that BKV may not be the etiological factor of BC. 118 Similarly, another multicenter case-control study from Italy did not reveal an association between BKV infection and BC etiology in immunologically individuals. 19In recent years, with the continuous deepening of research, the BKV sequence has been reported to originate from BC, and considerable evidence points to the possible involvement of BKV in the onset and development of BC. 118,119 Fioriti et al. analyzed bladder tissue from 32 patients with primary BC and revealed a significantly different proportion of human polyomaviruses compared to normal samples.
Especially, BKV has been shown to play an indispensable role in single infections and co-infections, suggesting its potential importance in the pathogenesis of BC. 100 In addition, BKV testing from 1135 subjects with new-onset BC from five regions in Spain revealed a higher median serum activity in BKV-positive cases than in controls.
These findings suggest that BKV infection increases the risk of BC. 120 Furthermore, the morbidity of BC was significantly higher in patients with renal transplant than in the general population.Moreover, kidney transplant recipients receive immunosuppressive therapy to minimize the occurrence of rejection reactions, which increases their susceptibility to infections, specifically viral infections.linked to BC in transplant recipients. 122BKV labeling triggers the activation of the DNA methylation transferase 1 gene, which in turn links the hypermethylation of tumor suppressor genes to the development of BC. 123,124 Decoy cells, a type of epithelial cell infected with BKV, exhibit morphological similarities to malignant cells and are considered a potential marker of BKV reactivation. 125A case study of a patient with BC who underwent kidney transplantation demonstrated positive staining for antibodies to T Ag protein, suggesting that BKV promotes BC progression in immunodeficient conditions. 126other study of polymorphic giant cell carcinoma of the bladder provides further evidence for the potential involvement of BKV in the oncogenic pathway. 127In addition, Bialasiewicz et al. 128 suggested that BKV is a potential causative factor for the development of BC.
Another study revealed similar findings, supporting the correlation between BKV and UC among kidney transplant recipients. 101,129rthermore, a recent large-scale study revealed a higher prevalence of BKV in patients with BC, albeit with a detection rate of only 7% and with predominantly low viral loads. 66Although early studies ruled out the role of BKV in BC, recent studies have revealed BKV as a potential cause of carcinogenesis of the bladder.However, with increased attention and diversified detection methods, the positive impact of BKV on the development of BC mandates further investigation.

| JCV AND BC
JCV is closely related to BKV and is a polyomavirus with a circular double-stranded DNA genome of 5.1 kb. 130,131The virus genome is mainly composed of three main regions: the early coding region encodes tumor antigens (t Ag and T Ag), the late coding region encodes capsid proteins (VP 1, VP 2, and VP 3), and the regulatory region. 132,133Based on the highly variable region of the coat protein VP1, JCV is classified into eight genotypes. 102,107,108These JCV genotypes have different geographic distributions: JCV types 1, 4, and 6 are widespread in Europe and the United States; types 2 and 7 are mainly found in Asia; type 3 is observed in South Africa, and type 8 is found in the Pacific islands. 134,135JCV adheres to a variety of Nlinked glycoproteins and enters the cell through clathrin-dependent endocytosis. 136In the nucleus, the T Ag binds to Rb, releasing E2F and forcing the cell into the S stage.In addition, the C-terminal of T Ag contains the p53-binding domain, which interacts with p53 and inhibits p53-induced apoptosis, leading to uncontrolled cell growth (Figure 2). 133,137JCV can survive in the kidneys for a long period after the initial infection without apparent symptoms. 105The primary infection of JCV usually begins in childhood, with seropositivity developing at the age of 10-15 years. 138Consequently, approximately 70%-80% of adults develop JCV-specific antibodies. 106ymptomatic viruria has been observed in healthy and immunocompromised individuals as well as pregnant women. 108Reportedly, JCV serves as a significant risk factor for progressive multifocal leukoencephalopathy in all immunosuppressed patients and 5% of people with AIDS. 139However, the oncogenic potential demonstrated by JCV latent in urinary epithelial tissue has led to an increased association between JCV and UC. 140Taiwanese study that examined tissue samples from 33 cases of UC revealed that JCV DNA was observed in 90.1% (30/33) of tissue samples, with large tumor antigen being observed in 30% (10/ 33) of the tissues.This suggests that JCV is highly prevalent in UC patients, indicating its role as a valuable etiological factor.141 Another case study of a kidney transplant recipient found that the patient developed JCV nephropathy 5 years later and UC 9 years later, with positive detection of JCV DNA in UC tissues.142 Given the strong association, Fang et al. transduced JC polyomavirus particles into human UC cells and observed a reduction in tumor nodules.These findings offer novel insights into the potential role of JC polyomavirus particles in the gene therapy of UC. 143 The existing studies, although limited, support a close correlation between JCV infection and BC progression.In the general population, a small minority of patients with BC have been found to carry the DNA virus.In contrast, solid organ transplant recipients have a higher probability of harboring the JCV and are thus at a higher risk of BC. 142 The persistence of JCV in the kidney and urinary tract after the initial infection and the constant oncogenic risk conferred by the virus in urothelial cells have gained considerable attention in the etiology of BC.However, the long duration between JCV infection developing into BC, the small number of cases, the multifactorial role of the other polyomaviruses, and the limited tools to investigate the underlying link between JCV infection and carcinogenesis have always hindered further development in this field.Consequently, more cases are required to elucidate the relationship between JCV infection and BC, as well as to elucidate the specific effects of JCV in the pathogenesis of BC.

| ONCOLYTIC VIROTHERAPY FOR BC
Currently, surgery, radiotherapy, chemotherapy, and immunotherapy remain the mainstay of BC treatment.However, with increasing challenges in managing advanced BC and rising mortality rates, several alternative therapeutic options are being assessed. 144netically engineered viruses designed to infect, replicate, and destroy tumor cells offer a more valuable treatment for cancer.An attractive approach would be to initiate tumor self-destruction in an immunogenic manner, which would promote tumor-antigen crosspresentation and induce tumor-specific adaptive immune responses. 145This goal can be achieved by intra-tumor delivery and expression of "suicide genes" that encode an enzyme that catalyzes the formation of highly toxic metabolites when administered with nontoxic prodrugs.The best known example is the combination of herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV). 146These modified viruses selectively target and replicate within the malignant cells, and ultimately killing them. 1479][150] Animal experiments revealed that oncolytic HSV viruses The results indicated that the therapy induced immunogenic tumor cell death both in vivo and vitro. 154The emergence of these novel therapies has provided new approaches to the management of BC.
Although the use of oncolytic virotherapy in the treatment of BC is becoming increasingly sophisticated, it is premature to establish such a therapy, 155 and further studies are required to replicate these findings in clinical scenarios.

| DISCUSSION
Viruses carrying potent oncogenes have the capability to induce carcinogenesis; however, the occurrence of virus-induced cancer in humans is considerably lower than the rate of viral infection, which can be attributed to the fact that viral infection is a required, but not sufficient, prerequisite for carcinogenesis.These viruses have the potential to persistently infect humans for decades, resulting in chronic damage to the immune system and immunosuppression while inducing chronic inflammation at the site of infection. 156,157On the one hand, prolonged chronic inflammatory stimulation accelerates the regeneration cycle of the urothelium, leading to permanent alterations. 24On the other hand, long-term latent strains reactivate when the human immune function is suppressed or severely compromised, ultimately resulting in tumorigenesis.BC, as the most prevalent malignancy of the urinary system, is one of the cancers associated with highest individual costs owing to the high rate of recurrence and progression. 158 addition to smoking, alcohol consumption, occupational exposure and genetic predisposition, 159 viral infections (especially HPV) have been identified as contributing factors in the etiology of BC. 26 Since the initial report by Kitamura et al. on the detection of HPV 16 in BC cases, numerous studies have assessed the role of HPV in BC. 160 Multiple surveys have reported the existence of HPV DNA in BC tissues, [51][52][53][54]161 which has been associated with disease progression. 27,5 A recent meta-analysis has demonstrated that HPV may be involved in the development and progression of BC, as well as contribute to the unfavorable prognosis of patients.41 Moreover, a study in Iran revealed that HPV positivity was as high as 71.4% in BC tissues and 33.6% in urine samples, which exhibited a significant correlation with both the grade and stage of cancer.57 However, another meta-analysis from Iran indicated a lack of notable correlation between HPV infection and BC. 67 Seeral studies have failed to establish a correlation between HPV and BC.[48][49][50]65,66 Consequently, the role of HPV determining HPV genotypes and integration status, which eliminates the drawback of PCR of only detecting specific primers.163 Using this technique, 17 subtypes of HPV in BC have been identified, of which HPV39 is a novel subtype to be identified.This demonstrates the criticality of developing a vaccine against this subtype.Furthermore, HPV infection in males with BC should be of concern as their female partners may be at potential risk for cervical cancer.164 Consequently, vaccination against HPV becomes imperative for both sexes.
HIV infection remains a prominent contributor to global morbidity and mortality.HIV exists in multiple subtypes, and recombination between these subtypes results in widespread epidemics. 73The progressive depletion of CD4+ T cells following infection results in severe immunodeficiency that subsequently manifests as characteristic infectious or neoplastic complications. 74vertheless, the available research does not appear to support the role of HIV infection in BC, as the incidence of BC in patient with HIV infection is significantly lower than that in the general population.
Although HIV may be associated with clinical progression in this subset of patients, there seems to be no obvious difference in prognosis.In fact, BC in HIV-infected patients has been poorly reported, and we have only limited data.In addition, significant difference exists in the age of two diseases.Advanced age is the overriding risk factor for BC, with the median age of onset between 70 and 84. 144,165However, only 7% of HIV patients are over 50 years old, and 81% of patients are aged 15-49 years old.Furthermore, current studies on the prevalence of BC in HIV-infected patients only consider AIDS patients, and may ignore HIV-infected people who receive ART, because they have a larger population base. 81It is worth noting that with the widespread application of ART therapy, the life expectancy of HIV-infected people has increased, and more BC may be observed in the future.There is no doubt that despite the success of ART therapies, HIV infection continues to spread at a rate of millions of individuals annually.7][168] Consequently, it is imperative to monitor the potential increase in the incidence of HIV-associated BC patients in the future.
HSV infection can exhibit latency in the urogenital tract and cause cellular atrophy, suggesting a causal link between HSV and BC.
Moreover, HSV frequently accompanies HPV infection, which further increases the risk of tumor formation.However, owing to the low prevalence of HSV in BC patients and the paucity of literature reports, the potential relationship between the two remains unclear.
Prospective, large-scale investigations of patients and controls are required to validate this issue.Interestingly, the use of HSV lysoviral therapy for BC has achieved satisfactory efficacy in BC, indicating that this therapy could be another significant breakthrough in cancer treatment following the success of immunotherapy using immune checkpoint inhibitors. 169However, HSV lysoviral therapy is currently limited to animal research, and there is an urgent need to confirm the feasibility of this therapy in the clinical setting.
Both BKV and JCV belong to the polyomaviridae family and are endemic in populations globally. 107Previous studies have shown that 70%-80% of adults are seropositive for BKV and JCV. 170Both can be latent in the kidney for a long time after the primary infection and are excreted in the urine.BKV has mainly been associated with the development of lung, pancreatic, liver, and urogenital tract cancers.
JCV is mainly associated with rectal and BC. 171Originally, BKV was thought to have no or a weak correlation with BC, probably due to the fact that most reports were isolated cases.Nevertheless, with the continuous advancement in sequencing technology and with the large-scale implementation of qRT-PCR and immunohistochemistry, viral infections in BC are gaining increasing attention.In the future, it is likely that the relationship between BKV, JCV, and BC will be better elucidated as probe capture and NGS methods are being developed to improve the sensitivity and specificity of detection, as well as an increasing number of related cases are being identified and reported.In addition, most of these patients were concentrated in immunocompromised recipients receiving kidney transplants.Consequently, for patients with autoimmune diseases, patients with cancer, and organ transplant recipients, screening for BKV and JCV may be performed before immunosuppressant or immunomodulator therapy. In are effectively inhibited against BC, with two moderate doses of the virus resulting in tumor of BC in most animals.This oncolytic HSV virus targets tumor cells selectively by activating the Ras signaling pathway, inducing tumor cell-specific immune response, and enhancing the overall antitumor activity.151However, this therapy is limited by its inherent neurotoxicity.Accordingly, Zhang et al.152 proposed a new microRNA regulatory approach to decrease HSV-1-induced neurotoxicity by inhibiting viral replication in neurons while retaining the tumorolytic effect on BC.Pourchet et al.153 have developed an oncolytic virus based on HSV-1 that produces bovine herpesvirus UL49.5 to effectively inhibits tumor growth, contralateral tumors, and metastatic foci.Hojeij et al. based on the ability to efficiently package DNA plasmids into HPV coat proteins upon HPV infection and the production of high titers of nonreplicating pseudoviral particles (PsV), testing the cancer-targeting ability of HPV PsV after intravenous administration to implement suicide gene therapy for BC.
conclusion, HPV-associated viral infections play an indispensable role in the progression and prognosis of BC.Although the correlation between HPV infection and BC continues to be debated for many reasons, we recommend considering HPV as a potential risk factor for UC in terms of histological subtypes.Other viruses, such as HSV, BKV, and JCV, have demonstrated correlations with BC in a limited number of cases; however, their contribution to the etiology of BC cannot be ignored.In addition, the rapid development of oncolytic viruses provides new treatment options for patients and clinicians, and combining them with other antitumor strategies may bring several unexpected benefits to patients.At the same time, we recommend that more attention is paid to the virology research in the development of BC and its potential value in treatment strategies.