Links between Human Papillomavirus, HSV, and Cervical Cancer

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Daniel Sausen	--	2363	2023-07-27 18:28:09	\|
2	layout	Jessie Wu	+ 11 word(s)	2374	2023-07-28 05:35:31	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers15143692

There is a significant body of research examining the role of human papillomavirus (HPV) in the pathogenesis of cervical cancer, with a particular emphasis on the oncogenic proteins E5, E6, and E7. What is less well explored, however, is the relationship between cervical cancer and herpes simplex virus (HSV). To date, studies examining the role of HSV in cervical cancer pathogenesis have yielded mixed results. Should this relationship be clarified, treating and preventing HSV could open another avenue with which to prevent cervical cancer. An overview of HSV and HPV infections and then delves into the possible links between HPV, HSV, and cervical cancer are discussed. It concludes with a summary of preventive measures against and recent treatment advances in cervical cancer.

HPV cervical cancer HSV

1. Relationship between Human Papillomavirus and Cervical Cancer

Dr. Harald zur Hausen first espoused the theory that human papillomavirus (HPV) was linked to cervical cancer in 1976 ^[1]. Since then, the link between HPV and cervical malignancy has been well established, with it being estimated that HPV is responsible for approximately 99.7% of cases of cervical cancer ^[2]. While more than 200 types of HPV exist ^[3], they are broadly categorized into two groups, low-risk HPV types that can cause genital warts and high-risk HPV types that are oncogenic in nature ^[4]. There are 14 high-risk strains of HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, and 68) ^[5]. Of these 14 high-risk strains, two strains, in particular, HPV-16 and HPV-18, account for approximately 70% of cervical cancer cases ^[6].

Several oncoproteins play a role in the pathogenesis of HPV-mediated cervical cancer, the most important of which are the E5/6/7 oncoproteins ^[7]. The structure of the HPV16 genome is 7.9 kb long and is divided into an early gene-coding region (E), a late coding region (L) and the long control region (LCR) ^[8]. In the early gene-coding region, there are six open reading frames, E1/E2/E4/E5/E6/E7 ^[8]. While E1/E2 play roles in controlling viral genome replication as well as early protein transcription, E5/E6/E7 are considered to be the main facilitators of oncogenesis ^[8].

E5 promotes oncogenesis through various mechanisms, such as disrupting the acidification of endosomes, thus enhancing EGF receptor recycling ^[9]. E5 also plays a role in promoting the upregulation of Met, a receptor tyrosine kinase that is implicated in facilitating tumor cell invasion ^[10]. In addition, E5 cooperates with E6 and E7 to enhance numerous pro-carcinogenic features. HaCaT cells transduced with E5/E6/E7 have more viable cells and proliferate faster than control cells ^[11]. Moreover, proliferation rates are faster in cells transfected with all three oncoproteins than those transfected with E5 or E6/E7 ^[11]. Cells transfected with E5/E6/E7 are also more invasive than control cells and those transfected with E5 or E6/E7 ^[11]. Transduction with the three oncoproteins alters the cellular redox state too; these cells have higher rates of peroxiredoxin when compared to control and E5 transduced cells. They also have a greater expression of the antioxidant GSH than all other cells ^[11]. Notably, high-risk and low-risk E5 proteins have different roles in HPV infection, and the difference is mediated by just two amino acids ^[12].

E6 promotes the degradation of p53 ^[13]^[14]. E6 also promotes the upregulation of IL-6, which in turn activates the JAK-STAT pathway and may stimulate a pro-inflammatory, pro-proliferative microenvironment ^[15]. Experiments with HPV-18 show that E6-mediated induction of STAT3 is essential in driving the cell cycle. Loss of STAT3 expression inhibits HPV gene expression and episome maintenance ^[16].

Recent research has analyzed other molecular targets of the E6 protein. Fan et al. demonstrated that HPV-16 E6 was capable of binding to the APOBEC3B promoter to upregulate its expression. They showed that this protein was highly expressed in HPV-16/-18-associated cervical cancer and was associated with the development of metastatic disease ^[17]. Importantly, APOBEC3B expression was found to result in hypomethylation of the promoter for CCND1, which codes for cyclin D1 ^[17]. Cyclin D1 is a key regulator of the cell cycle and controls the G1/S transition ^[18].

The c-Jun N-terminal kinase (JNK) pathway is another target modulated by E6 ^[19]. JNK1/2 phosphorylation increases in cervical cancer tissue when compared to control tissue. E6 stimulates JNK1/2 phosphorylation through the E6 PDZ-binding motif ^[19]. JNK inhibition results in a concomitant decrease in c-Jun phosphorylation and expression, as well as a decrease in cell growth. This inhibition is not noted in the HPV-negative cell line C33A ^[19]. The JNK/c-Jun pathway promotes the expression of transcription factors required for epithelial/mesenchymal transition (EMT), such as Slug. It also promotes the expression of the mesenchymal marker vimentin. Matrix metalloproteinase 9, a key pro-invasive enzyme, is downregulated following JNK inhibition. This signaling path is needed for the constitutive expression of E6 and E7 ^[19]. Mechanistically, the activation of the JNK pathway leads to increased EGFR signaling, which in turn leads to cell survival, proliferation, and EMT ^[19].

Low levels of the microRNA (miR) hsa-miR-504 are associated with both the development of cervical cancer and a poor prognosis ^[20]. This represents another target of the E6 protein ^[21]. E6 overexpression in the cervical cancer line SiHa results in significantly lower levels of miR-504. Overexpression of E6 also augments the proliferative and invasive abilities of SiHa cells and inhibits apoptosis, changes reversed with miR-504 overexpression ^[21].

Recent research has begun to explore the role of long non-coding RNAs (lncRNA) in carcinogenesis ^[22]^[23]. One such lncRNA implicated in the pathogenesis of cervical cancer is lnc_000231, which is upregulated in cervical cancer ^[24]. E6 upregulates the expression of lnc_000231. The mechanism through which this upregulation occurs involves promoter H3K4me3 modification. Specifically, E6 destabilizes the histone demethylase KDM5C. The increased lnc_000231 expression results in lower levels of miR-497-5p, which in turn results in higher expression levels of cyclin E1, which is involved in the G1/S transition ^[25]. Notably, lnc_000231 knockdown stunts cell growth, cell colony formation and cell cycle progression in vitro and inhibits tumor formation in vivo ^[25].

E7 plays a role in promoting IL-6 expression, although its effect is less than E6 ^[15]. The E7 oncoprotein targets pRB and facilitates its degradation, causing activation of E2F transcription factors and subsequent downstream genes promoting cell proliferation ^[26]. Moreover, E7 can impair p53 function even in the absence of E6 ^[27].

Like with E6, recent research analyzed novel molecular targets of E7. Phosphorylated AKT and phosphorylated SRC both have higher levels of expression in cervical cancer, including higher levels in invasive samples than in precancers ^[28]. Knockdown of HPV-16 E7 protein results in diminished expression of phosphorylated AKT (p-AKT) and phosphorylated Src (p-SRC), while E7 expression results in increased levels of these two proteins. Notably, E7 is continually expressed to maintain elevated levels of p-AKT and p-SRC. Indeed, HPV-16 E7 leads to the expression of p-AKT and p-SRC, which then stimulates the initiation and progression of cervical cancer ^[28].

In addition, high-risk E7 was shown to stimulate cervical cancer cell proliferation and migration. It increases levels of topoisomerase II α (TOP2A), BIRC5, and E2F1 ^[29]. Inhibition of E2F1 results in decreased levels of TOP2A and BIRC5 and subsequent inhibition of migration and proliferation of cervical cancer cells. E7 results in the upregulation of E2F1, which subsequently enhances BIRC5 and TOP2A expression ^[29]. TOP2A expression is positively correlated with cervical cancer ^[30] and is overexpressed in many human malignancies ^[31]. BIRC5, also known as survivin, is an anti-apoptotic protein that is common in cancer ^[32].

E7 targets the promoter of the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) ^[33], a lncRNA that has been associated with cervical cancer progression ^[34]^[35]. Overexpression of HPV-16 E7 increases MALAT1 when transfected into HPV-negative HEK-293T and C33A cells, and E7 knockdown in the human cervical carcinoma lines CaSki and SiHa results in decreased MALAT1 expression ^[33]. Subsequent experiments demonstrate that this effect is mediated through the MALAT1 promoter ^[33]. Notably, small interfering RNA (siRNA) targeting MALAT1 reverses the enhancements in cell proliferation, invasion, and migration mediated by E7 ^[33]. E7 also enhances the expression of lnc-EBIC ^[36]. Overexpression of this lnc in HPV-negative C33A cells enhances proliferation, migration, invasion, and survival ^[36]. In addition, lnc-EBIC results in enhanced expression of the oncogenic Kelch domain-containing 7B (KLHDC7B), a finding corroborated by the fact that KLHDC7B knockdown strongly inhibits lnc-EBIC-mediated tumorigenesis in C33A cells ^[36].

2. Targeting Human Papillomavirus and Herpes Simplex Virus for the Prevention of Cervical Cancer

Cervical cancer is one disease for which there are robust prophylactic measures in place. The mainstay of prophylaxis is the highly effective HPV vaccine ^[37]. Furthermore, screening can be used to identify and treat precancerous lesions, thus preventing progression to carcinoma ^[38].

While the relationship between cervical cancer, HPV, and herpes simplex virus (HSV) is not yet precisely defined, a causative relationship would open another avenue for cervical cancer prophylaxis. Both prophylactic and therapeutic treatment of HSV would reduce the incidence of genital lesions, thereby limiting HPV’s ability to access the basal layer. As was mentioned above, this access is a key step in establishing HPV infection ^[39]. Prophylaxis would additionally prevent any pre-malignant changes induced by HSV-2 infection.

2.1. Prophylaxis and Early Detection of Oncogenic Human Papillomavirus

As previously mentioned, vaccination against HPV is highly effective in preventing cervical cancer ^[37]. An analysis of 1,672,983 Swedish girls and women aged 10–30 demonstrated that cervical cancer had an incidence of 47 cases per 100,000 patients in individuals vaccinated with the quadrivalent HPV vaccine. Non-vaccinated individuals had a much higher incidence of 94 cases per 100,000 people ^[37]. A separate study found that the quadrivalent HPV vaccine had an efficacy of 95.4% against persistent infection with the common high-risk strains, HPV-16 and HPV-18, following a single dose ^[40]. A meta-analysis further confirmed the efficacy of the HPV vaccine, both in those with no prior exposure and in those previously exposed to HPV-16/18 ^[41]. However, there are several barriers to vaccination, including cost, limitations imposed by infrastructure, and social stigma ^[42]. The barriers to vaccination are particularly high in lower-income countries, given their relatively limited screening and vaccination capacities ^[42].

There have been three vaccines approved for use in the United States. Gardasil was approved in 2006 and provides coverage against the low-risk strains HPV-6 and HPV-11, as well as the high-risk strains HPV-16 and HPV-18 ^[43]. It was originally approved for females aged 9–26 and has since been approved for both genders through age 45 ^[43]. In 2009, the bivalent vaccine Cervarix, which protects against HPV-16 and HPV-18, was approved for females aged 10–25 ^[43]. In 2014, the 9-valent Gardasil 9TM (9vHPV) vaccine was approved, with protection against HPV-6, -11, -16, -18, -31, -33, -45, -52, and -58 ^[43]. Notably, the 9-valent vaccine has been the only vaccine used in the United States since 2016 ^[42]. All HPV vaccines are created from the L1 capsid protein ^[44], which is capable of self-assembling into immunogenic virus-like particles ^[44]^[45].

The other key component of cervical cancer prophylaxis is screening. The US Preventive Services Task Force currently recommends cytologic screening for cervical cancer every 3 years in females aged 21–29 ^[46]. Between the ages of 30 and 65, women can either continue cytologic screening every 3 years or undergo testing for high-risk HPV +/− cytology every 5 years ^[46]. Patients younger than 21 should not be screened, and there is no indication to screen patients over 65 with a sufficient history of prior screenings unless they have an increased risk of developing cervical cancer ^[46]. However, like with vaccines, there are barriers to the implementation of a routine screening program in both low- and high-income countries ^[47]^[48].

2.2. Prophylaxis and Treatment of Herpes Simplex Virus Infection

The primary therapeutic option for HSV infection is acyclovir/valacyclovir ^[49]^[50]. Many alternatives exist, including valacyclovir, penciclovir, and famciclovir. These drugs are nucleic acid analogs that interfere with viral DNA polymerase ^[51].

In addition to the established antivirals, there are exciting new therapies emerging as potential treatment options. One such compound is ginkgolic acid, a product of the Ginkgo biloba tree. This compound has been shown to inhibit fusion across multiple classes of viral fusion ^[52]. HSV-1 was among the viruses inhibited by ginkgolic acid ^[52], and it is not unreasonable to assume that HSV-2 may be inhibited in a similar fashion. Brincidofovir, a lipid conjugate of cidofovir, was shown to act synergistically with acyclovir to inhibit HSV replication both in culture and murine models ^[53]. More recently, its efficacy in preventing breakthrough HSV infection was assessed in the setting of hematopoietic stem cell transplant recipients. Initial results were promising, with a reported rate of 1.0 per 1000 patient days ^[54]. Amenamevir is a helicase-primase inhibitor that showed comparable efficacy to valacyclovir in treating mice cutaneously inoculated with HSV-1. Furthermore, it demonstrated efficacy when applied on day 4 post-infection, something not seen in mice treated with valacyclovir ^[55].

Prophylactic measures against HSV are also under research. For example, Dropulic et al. administered the replication-deficient HSV-2 vaccine HSV529 to adults without either HSV-1 or HSV-2, with HSV-2 and with or without HSV-1, and with HSV-1 but without HSV-2. In total, 78% of patients without either virus had at least a four-fold increase in their titers of neutralizing antibodies, a response not seen in either of the other groups. In previously seronegative patients, CD4+ T cell responses were noted in 36% of patients compared to 46% in the group infected by HSV-2 +/− HSV-1 infection and 27% of the patients infected by HSV-1 but not HSV-2. CD8+ T cell responses were noted in 14%, 8%, and 18% of patients in these groups, respectively ^[56]. mRNA vaccines have also been assessed as prophylactic measures against HSV-2 in murine models. Mice vaccinated with an mRNA vaccine, including glycoproteins gC, gD, and gE, did not develop genital disease following challenge with HSV-1 or HSV-2. Vaginal swabs were positive for HSV-1 in 4/10 and for HSV-2 in 0/5 mice at the lowest challenge dose 5 × 10⁴ plaque-forming units. Day 2 swabs were positive for HSV-1 in 5/5 mice and for HSV-2 in 3/5 mice at 2 × 10⁵ plaque-forming units. Swabs were positive for HSV-1 in 12/15 and for HSV-2 in 5/10 mice at 2 × 10⁶ plaque-forming units. Only 3/30 HSV-1-infected mice and 1/20 HSV-2-infected mice had positive titers 4 days after infection. Importantly, no HSV DNA was detected in the dorsal root ganglia of any mouse that received the mRNA vaccine ^[57].

The VOICE trial is a clinical trial that assessed the efficacy of tenofovir, an adenine nucleotide analog reverse transcriptase inhibitor, in preventing the acquisition of HSV-2. Patients were instructed to apply tenofovir 1% gel once daily. There was a trend towards a reduced risk of seroconversion with HSV-2, although the results were not statistically significant, with a hazard ratio of 0.60 (95% CI, 0.33–1.08; p = 0.086). This ratio was adjusted for location, age, HIV status, hormonal contraception use, having at least two male sex partners in the last 3 months, and having anal sex in the past 3 months ^[58].

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Subjects: Virology

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Elisa S. Gallo

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Update Date: 28 Jul 2023

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