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Received: 24 August 2023
|
Accepted: 2 November 2023
DOI: 10.1002/jmv.29236
REVIEW
HPV co‐infections with other pathogens in cancer
development: A comprehensive review
Elahe Akbari |Alireza Milani |Masoud Seyedinkhorasani |Azam Bolhassani
Department of Hepatitis and AIDS, Pasteur
Institute of Iran, Tehran, Iran
Correspondence
Azam Bolhassani
Email: azam.bolhassani@yahoo.com and
A_bolhasani@pasteur.ac.ir
Abstract
High‐risk human papillomaviruses (HR‐HPVs) cause various malignancies in the
anogenital and oropharyngeal regions. About 70% of cervical and oropharyngeal
cancers are caused by HPV types 16 and 18. Notably, some viruses including herpes
simplex virus, Epstein–Barr virus, and human immunodeficiency virus along with
various bacteria often interact with HPV, potentially impacting its replication,
persistence, and cancer progression. Thus, HPV infection can be significantly
influenced by co‐infecting agents that influence infection dynamics and disease
progression. Bacterial co‐infections (e.g., Chlamydia trachomatis) along with bacterial
vaginosis‐related species also interact with HPV in genital tract leading to viral
persistence and disease outcomes. Co‐infections involving HPV and diverse
infectious agents have significant implications for disease transmission and clinical
progression. This review explores multiple facets of HPV infection encompassing the
co‐infection dynamics with other pathogens, interaction with the human micro-
biome, and its role in disease development.
KEYWORDS
cervical cancer, co‐infection, HPV, HPV‐related cancers, microbiome, viral pathogens
1|INTRODUCTION
Human papillomaviruses (HPVs) are the most common sexually
transmitted viruses which cause different disorders in women and
men such as precancerous lesions and different cancers.
1
In 1933,
HPVs were described as a large family of DNA viruses.
2,3
Viral
genome encodes core and accessory proteins. Core proteins have a
major role in viral genome replication (E1 and E2: early proteins) and
also virus assembly (L1 and L2: late proteins). These proteins are
highly conserved among all types of papillomaviruses. In contrast,
the accessory proteins (E4, E5, E6, and E7: early proteins) possess
more variability in their expression time and functional properties.
These proteins modify the infected cells to facilitate viral replication
in different diseases‐papillomavirus type relationships.
4
To date,
more than 200 HPV types have been identified. They were divided
into Alpha, Beta, Gamma, Mu, and Nu genera.
5
Notably, HPVs are
categorized as either 15 HR‐HPV/oncogenic types which can be
potentially carcinogenic, or 12 low‐risk (LR) HPV/nononcogenic
types which are often found in warts.
6
Although most HPV infections
are benign, persistent infection with one of the carcinogenic HR‐
HPV types is the main cause of cervical cancer. HPV types 16 and 18
are the most carcinogenic HPVs responsible for ~70% of cervical
cancer cases.
7
Moreover, several biological and environmental co‐
factors including tobacco usage, parity, hormonal changes, dietary
habits, immune level, and co‐infection with other pathogens were
involved in the progression of HPV‐associated cancers.
8
In 2020,
around 604 127 individuals received a new diagnosis of cervical
cancer, and 34 1831 lost their lives to this ailment on a global scale.
Regrettably, a significant majority of both new cases and fatalities,
ranging from 85% to 90%, have taken place in countries categorized
J Med Virol. 2023;95:e29236. wileyonlinelibrary.com/journal/jmv © 2023 Wiley Periodicals LLC.
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https://doi.org/10.1002/jmv.29236
Elahe Akbari and Alireza Milani are the first authors.
as less developed.
9
In co‐infection, the existence of one infectious
agent modifies the natural history of another one. Interactions of
HPVs with viruses or bacteria that share a similar epithelial niche
or transmission routes could increase HPV replication and
persistence, and accelerate cancer progression. Indeed, a history
of prior sexually or orally transmitted infections including human
immunodeficiency virus (HIV), herpes simplex virus (HSV),
Epstein–Barr virus (EBV), and different oral and cervicovaginal
bacteria led to a decreased ability for HPV clearance or an
increased risk of HPV infection.
8
Co‐infection with multiple
genotypes was usually detected in HPV HPV‐positive subjects,
as well.
10
In this review, the transmitted infectious agents as
potential risk factors in HPV‐related cancers are discussed.
2|EPIDEMIOLOGY
HPV infection is currently a global public health priority especially
among women.
11
The global HPV prevalence was estimated about
11.7%. The highest HPV prevalence was detected in Caribbean,
Eastern Africa, Eastern Europe, South Africa, and Western Europe.
Female sex workers are among the most susceptible groups to
HPV infections mainly HPV types 16, 52, and 53.
12
Table 1
represents the prevalence of HPV types 16/18 in women with
healthy cervical cell samples and precancerous cervical abnormali-
ties in some continents and subregions. The most prevalent HR‐
HPV types in the world include the HPV genotypes 16, 18, 59, 45,
31, 33, 52, 58, 35, 39, 51, 56, and 53, respectively. Also, the most
common LR‐HPV types are the HPV genotypes 6 and 11 causing
genital warts.
18
Table 2indicates the prevalence of type‐specific
HPVs in women worldwide.
3|HPV LIFE CYCLE
ThelifecycleofHPVcontainsestablishment, maintenance, and
vegetative/productive amplification phases, respectively. The establish-
ment phase includes viral transcription and genome amplification in the
basal layer. After the entry into the cells, the virus requires the expression
of E1 and E2 genes to maintain a low number of copies of the genome.
24
After the initial establishment phase, the viral genome maintains a
constant copy number. Indeed, it is replicated approximately once during
the DNA synthesis phase (S phase) of infected cells and distributed to
daughter cells during cell division.
25
In this phase, the E6 and E7 proteins
are expressed in the suprabasal layer. The E7 protein degrades
retinoblastoma (Rb) family members (i.e., p105, p107, and p130) leading
to the release of the E2F transcription factor which promotes gene
expression in the S phase, and elicits hyperproliferation.
26
Viral assembly
occurs in the maturing squamous epithelium leading to the release of
amplified viruses from the terminally differentiated squamous cells. This
3‐week process refers to the maturation of a basal cell to the superficial
cells.
27
In the granular layer, the L1 and L2 proteins known as the major
and minor capsid proteins respectively, assemble to form new virions.
These new virions are released from the epithelial cornified layer.
28
4|HPV AND IMMUNE EVASION
HPVs possess several mechanisms to escape from host immunologic
responses and establish the HPV‐related lesions
29
including (a)
Coordination of viral replication to cellular differentiation: HPV
regulates its own replication with differentiation of the keratinocytes.
Moreover, virions are released through the mechanical breakage of
surface epithelium minimizing inflammatory responses
30
;(b)
TABLE 1 Incidence of HPV 16/18 in females with healthy cervical cell samples and precancerous cervical abnormalities in some continents
and subregions.
Continent/Subregion
Normal cytology Low‐grade lesions High‐grade lesions
Number
of tested
95% confidence
interval
Number
of tested
95% confidence
interval
Number
of tested
95% confidence
interval
African 19 726 3.8 465 24.9 399 38.6
Eastern Africa 4115 4.7 150 30.0 138 45.7
Americas 105 042 4.5 9893 26.7 13 590 56.9
South America 10 180 5.8 2191 35.6 2516 56.3
Asia 142 676 3.4 7959 21.2 13 444 42.1
Southern Asia 14 520 4.4 225 30.2 287 63.4
Europe 180 090 3.8 19 401 27.1 21 140 54.5
Eastern Europe 86 821 4.2 4,949 30.6 8448 54.9
Oceania 2997 8.3 473 27.1 1629 597.1
Australia & New Zealand 2271 8.5 473 27.1 1517 58.4
Abbreviation: HPV, human papillomavirus.
Source: Guan and colleagues.
13–17
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AKBARI ET AL.
Maintenance of viral antigens (i.e., early viral gene products) in low
levels controlled by E2 protein, and the lack of HPV proteins' secre-
tion: During disease progression, the HPV genome is integrated into
the host genome leading to the disruption of the E2 locus and thus
high expression of E6 and E7 proteins in high‐grade lesions and
cancer.
31,32
The low levels of early viral proteins can hamper the
detection of HPV‐infected cells by local antigen‐presenting cells
named as Langerhans cells (LCs), and thus suppress the stimulation of
an effective adaptive immune response against these infected cells
33
;
(c) Direct inhibition of both innate and adaptive immune cell function:
Most cells of the innate immune system express pathogen
recognition receptors such as toll‐like receptors (TLRs), NOD‐like
receptors (NLRs), and RIG‐I‐like receptors.
34–37
Furthermore, cyclic
GMP‐AMP synthase, a major cytosolic DNA sensor,
38
activates
STING (stimulator of interferon [IFN] genes) leading to transcription
of IFNs, chemokines, and cytokines, and thus induction of an antiviral
response.
39
For example, Hasan et al. showed that HPV16 E7
downregulates TLR9 in human epithelial cells by activating histone
demethylase JARID1B and histone deacetylase 1 and thus suppress-
ing IFN responses.
40
It was also reported that HPV18 E7 binds to
STING and inhibits upregulation of IFNs in the presence of cytosolic
DNA. In contrast, HPV16 E7 escapes from STING‐induced IFN
activation through the NLRX1 (NLR family member X1) protein.
24
5|CANCER‐RELATED HPVS
HPVs cause both premalignant and malignant lesions in different
tissues (e.g., cervical, anogenital, oropharyngeal cancers (OPC);
esophageal carcinoma)
3
(Table 3). Cervical cancer cases are often
related to HPV infections. For instance, the highest risk of cervical
intraepithelial neoplasia (CIN) was associated with HPV types 16 and
33 followed by HPV types 18, 31, and 45.
46
Head and neck, vulvar,
and esophageal squamous cell carcinoma (SCC) (i.e., head and neck
squamous cell carcinomas [HNSCC], vulvar squamous cell carcinoma,
and esophageal squamous cell carcinoma) are often related to HPV
type 16 followed by HPV type 18 and other strains (e.g., HPV types
31, 33, and 45).
47–50
6|DIAGNOSIS AND TREATMENT
The diagnosis of HPV infections is the most important step for
control of HPV‐related diseases.
51,52
The effective techniques for
HPV detection and regular screening include Pap smear, biopsy,
acetic acid test and colposcopy, nucleic acid detection using
polymerase chain reaction, southern blot hybridization, and in situ
hybridization
53
as shown in Table 4. Serological tests are not useful
for HPV infection due to poor serological response of host.
54
The
HPV nucleic acid test is one of the accurate tests for HPV diagnosis in
women. On the other hand, it is worth noting that there is currently
no approved test specifically designed for HPV diagnosis in males.
Nevertheless, clinical diagnosis can utilize HPV mRNA or DNA in situ
for this purpose. Routine screening for HPV‐related diseases in men
is not presently recommended by the Centers for Disease Control
and Prevention‐USA.
55,56
Sometimes, an anal Pap test may be
performed for men with a high risk (HR) of developing anal cancer.
1
On the other hand, the management and treatment of HPV‐
related diseases are largely influenced by various factors including
the specific types of HPVs, the availability of treatments, and the
TABLE 2 Type‐specific HPV prevalence in women with normal cervical cytology, and precancerous cervical lesions in the World.
HPV type
Normal cytology Low‐grade lesions High‐grade lesions
Number of
tested
95% confidence
interval
Number of
tested
95% confidence
interval
Number of
tested
95% confidence
interval
High‐risk HPV type
16 453 184 2.8 38 177 19.3 50 202 45.1
18 440 810 1.1 37 748 6.5 49 743 6.8
31 415 367 1.2 36 170 7.7 48 538 10.4
33 413 075 0.7 35 733 4.7 48 592 7.3
35 396,307 2.8 31 095 3.0 44 703 3.3
Low‐risk HPV Type
6 418 946 0.9 26 981 6.2 34 563 2.3
11 406 162 0.5 26 179 2.9 33 547 1.3
40 186 634 0.3 4379 1.5 11 872 0.4
42 326 078 0.6 4932 7.1 9543 1.3
43 259 930 0.2 3258 1.7 5549 0.4
Abbreviation: HPV, human papillomavirus.
Source: Maranga and colleagues.
19–23
AKBARI ET AL.
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progression of the disease.
57
There are currently three HPV
prophylactic vaccines (e.g., Cervarix, Gardasil, and Gardasil‐9) that
are safe and effective in preventing cancer‐related HPV infections
58
;
but unfortunately, there is no licensed therapeutic vaccine. Thus, the
prophylactic HPV vaccination is considered as an additional
treatment in patients with recurrent HPV‐related diseases.
59
It is
hypothesized that such vaccination may stimulate cell‐mediated
immunity, which can play a role in preventing recurrent HPV
infections.
60
Several reports showed that adjuvant HPV vaccination
is related to a decreased risk of active HPV‐related diseases,
especially CIN recurrence.
59,61,62
The primary objective of treatment
is to alleviate symptoms, remove the transformation zone of warts or
lesions, and minimize the risk of future invasive cancers.
63
Unfortunately, there is currently no certain evidence regarding the
complete treatment of HPV‐related diseases.
57
In the cases of
infection with nononcogenic HPVs, recommended treatments for
external genital warts are topical medicine (e.g., Podophyllotoxin,
Imiquimod, Sinecatechins, and Trichloroacetic acid).
63–66
Some
limited therapies such as 5‐fluorouracil, intralesional/topical IFN,
and photodynamic therapy are also recommended.
67–69
Moreover,
surgery, chemotherapy, radiotherapy, targeted therapy, or their
combination are available therapies for treatment of HPV‐related
cancers.
62
In the recent years, several studies have suggested that
complementary treatments such as probiotics are useful in clearance
of HPV infections. Indeed, probiotics can stimulate the production of
antimicrobial peptides and anti‐inflammatory cytokines, prevent
bacterial adhesion and acidification, and subsequently reduce
bacterial vaginosis (BV) and sexually transmitted diseases.
70–72
7|HPV CO‐INFECTIONS
Different groups of pathogens (e.g., bacteria, viruses, protozoa, and
fungal parasites) infect human, and they often co‐occur within
individuals.
73
Co‐infection involves globally important infectious
agents such as HPV, HIV, tuberculosis, hepatitis, leishmaniasis, and
dengue fever.
74
The true prevalence of co‐infection in infectious
diseases exceeds one‐sixth of the global population.
75
In co‐infection,
pathogens can interact either directly with one another or indirectly
through the host's resources or immune system. These interactions
within co‐infected hosts change the transmission, clinical progression
and control of multiple infectious diseases compared to single
pathogen infections.
76,77
HPV infection (a main risk factor for human
malignancies) often increases the risk of co‐infection with other
infectious agents such as viruses and bacteria.
74
A brief discussion of
these co‐infections is described in the next sections.
8|CO‐INFECTION OF HPVS WITH
OTHER VIRUSES
As mentioned earlier, development of HPV‐associated dysplasia is
strongly associated with chronic or persistent HR‐HPVs infections.
8
However, it is worth noting that such infections typically resolve
spontaneously by the immune system. Moreover, the risk of
developing cancer in HR‐HPVs infection is low.
78,79
For example, in
the case of cervical cancer, only <1% of HPV
+
women will develop
neoplasia.
8
Thus, additional biological and environmental risk factors
like co‐infection with other infectious agents may reduce the host
ability to clear HPV or increase the risk of HPV infection‐related
malignancies.
80
Several studies reported that different viruses with
the same epithelial niche may interact with HPV leading to an
increased HPV replication and persistence, and thus accelerating
cancer progression.
8
We will review several viruses as potential risk
factors in HPV‐related neoplasia in the next sections. Among them,
HIV was known as the most important virus associated with HPV
infections.
8.1 |HPV and herpes‐simplex virus co‐infection
The herpesviridae family includes the enveloped double‐stranded
DNA viruses (i.e., HSV, EBV, Cytomegalovirus [CMV] and human
herpesvirus 6 and 8 [HHV‐6 & 8]).
81
They can establish lifelong latent
infections in the host.
82
The latent herpesviruses can be reactivated
in response to stress, and cause secondary infection in epithelium for
productive viral replication and shedding.
8
These viruses replicate
generally in the epithelial cells of the oral cavity and genital tract.
83
Different reports showed the implication of herpesviruses in
increasing the risks of cervical dysplasia.
82,83
Co‐infection of HPV
with members of herpesviridae especially HSV and EBV was also
reported in different studies.
83–85
Regarding HSV, there are two viral
TABLE 3 Some characteristics of HPV‐related cancers in the world.
Cancer Localization Sex Age (year) New cases of HPVs‐related cancers in 2020 References
Cervical cancer Cervix Women 15–44 604 127 [41]
Oropharyngeal cancer Head and neck Men and women Mean age: 68 98 412 [42]
Vulvar squamous cell carcinoma Skin Men and women Mean age: 70 45 240 [43]
Penile cancer Penis Men 50–70 36 068 [44]
Esophageal cancer Esophagus Men and women Mean age: 65 604 100 [45]
Abbreviation: HPV, human papillomavirus.
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AKBARI ET AL.
genotypes of HSV‐1 and HSV‐2 that are distinguished by envelope
antigenic differences, and cause common oral and genital infections
worldwide.
80
Although both viruses are a significant source of
diseases all over the world, HSV‐1 is more seroprevalent.
86
HSV‐1
and HSV‐2 can be transmitted by close personal contact with an
individual shedding and attacking oral and genital mucosa, respec-
tively.
80
Thus, HSV‐2 is more frequently linked to recurrent genital
herpes.
81
Different epidemiological investigations have indicated the
correlation between HSV and HPV infections.
80,85
High incidence
rates for such co‐infections were observed because of direct contact
with lesions or with HSV‐infected oral or genital secretions during
asymptomatic shedding that may enable HPV to transmit and access
the basal cell layer more profoundly.
87
It was proposed that the
replication of HSV in tissues where HPV also replicates may have a
direct or indirect impact on the persistence, clearance, and/or
oncogenic potential of HPV.
8
According to different reports, HSV‐2
positive cases have a 2‐to 9‐fold higher chance of experiencing
cervical SCC or adenocarcinoma than HSV‐2 negative ones.
85
Furthermore, HPV/HSV‐2co‐infection in cervical intraepithelial
neoplasia and SCC was strongly higher than in healthy women.
88
Comparatively to 0%–4% of healthy cervical tissues, HSV‐2
co‐infection with HPV types 16 and 18 was observed in 25%–30%
of CIN and 13%–25% of invasive cervical SCC and adenocarcino-
mas.
88
A cross‐sectional study in 2020 reported a significant
difference in HSV‐2 seroprevalence and HSV‐2 active infection rates
between negative and positive HR‐HPVs cases.
89
Additionally, HSV‐
2 can boost transmission of HIV‐1, EBV, or other sexually transmitted
pathogens, thus helping the HPV infection and persistence in this
way.
90
HSV‐2 and HIV‐infected women were reported to have
cervicovaginal inflammation, and harbor a high diversity of microbes
leading to more susceptibility to HPV infection.
91
HPV/HSV‐2co‐
infection interferes with local immune responses, which increases the
likelihood of HPV‐related lesions progression.
92
A few studies
reported co‐infection of HPV, EBV, and/or HSV in different
anatomical sites like anorectum, oral cavity, oropharynx, and
urethra.
90
A similar correlation between HSV‐1 and HPV was
observed in HNSCC. For example, HPV‐16/HSV‐1co‐infection in
patients with HNSCC showed the worst disease outcome.
90
In
addition, HSV‐1 infection may increase the radiation resistance of
HPV16‐positive cancer cells by improving cell survival and preventing
apoptosis.
93
Previous studies demonstrated that HSV‐1 interferes
with DNA repair mechanism in the cells leading to some genetic
changes during the process of acute lymphoblastic leukemia.
88
Additionally, HSV infections induce permanent genetic alterations
through unexpected cellular DNA synthesis and chromosomal
amplifications that interfere with the differentiation of the cervical
epithelium, and subsequently induce abnormal proliferation as an
HPV co‐factor.
83
In vitro studies suggested that HSV may contribute
to the process of HPV carcinogenesis without the need for continued
presence (hit‐and‐run theory). This scenario explains that HSV
replication makes significant cytopathic effects in HPV‐infected cells,
and also can reduce HPV E2, E6, and E7 expression and DNA
replication.
8
Transient infection by HSV leaves lasting molecular
TABLE 4 Screening and diagnosis of HPV‐related pathogenesis.
Type Characteristic Method Clinical sensitivity Principle
Nonmolecular techniques Cell morphology Visual inspection Low Visual inspection of the cervix
Colposcopy Moderate Stereoscopic and magnified viewing of the cervix
Cytology and histology High Examining of individual cells or an entire section of tissue
Molecular techniques HPV nucleic acids PCR High Amplification of viral sequences present in the biological specimen
Hybridization High Formation of specific HPV DNA‐RNA hybrids, which are then captured by antibodies
Southern and Northern blot Moderate Hybridization (southern blot for DNA and northern blot for RNA molecules) with specific
HPV probes
In situ hybridization Moderate Identifying specific nucleotide sequences in cells or tissue sections with conserved
morphology
Serological assays Anti‐HPV antibodies Detection of capsid antibody Low Identifying HPV by VLP‐based ELIZA
Neutralization assays Low Neutralizing epitopes by monoclonal antibodies
Detection of antibodies to HPV proteins Low Using HPV E6, E7 proteins as antigens in either ELIZA or western blot analysis
Abbreviation: HPV, human papillomavirus; VLP, viral‐like particles.
AKBARI ET AL.
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changes that enhance oncogenic potential of HPV. For example, HSV
can activate AP‐1 (activator protein‐1) pathway by inducing the
expression of viral immediate early genes such as infected cell protein
0 which can directly interact with AP‐1 transcription factors. This
activation of AP‐1 can lead to the upregulation of genes involved in
cell cycle progression, antiapoptotic signaling, and angiogenesis, all of
which contribute to tumorigenesis.
94
Under this scenario, detailed
research is needed to better understand the biological mechanisms
underlying the HPV/HSV co‐infection.
8.2 |HPV and EBV co‐infection
EBV is a herpesvirus found in B‐cells and epithelial cells that infects
over 90% of adults globally.
95
While primary infection often causes
no symptoms or mild mononucleosis, EBV establishes lifelong latent
infection in B lymphocytes and oropharyngeal and salivary gland
epithelial cells.
79,96
This latent infection is related to several
malignancies including Burkitt's lymphoma, Hodgkin's disease, non‐
Hodgkin's lymphoma, HNSCC.
90
According to different reports, EBV
DNA was detected in more than 60% of invasive SCC with a strong
association with lesion severity.
8
The mechanisms of EBV in
carcinogenesis are complex including induction of a local immune
suppression, and immortalization of infected cells via manipulation of
the cell cycle and apoptosis pathways.
79
Malignant transformation and
tumorigenesis in epithelial and lymphoid tissues are started by
targeting several host cellular pathways mainly through EBV proteins
such as latent membrane proteins (LMP‐1and‐2), BamHI‐A rightward
frame 1 (BARF1) and EBV‐encoded nuclear antigens (EBNAs) and small
noncoding ribonucleic acids (EBER‐1and‐2).
96,97
It is also hypothe-
sized that EBV‐related cancers may arise from the reactivation of the
virus, potentially triggered by the influence of co‐factors such as
concurrent infections.
97
The immunosuppression and chronic antigenic
stimulation by EBV reactivation can result in viral replication, spread,
and establishment of new latent viruses in other cells that contribute
to the development of oncogenesis.
96
Interestingly, EBV and HR‐HPVs
co‐infection is frequently detected in different cancers especially oral
cavity cancers (OCC).
96,98
In 2022, Rahman et al. reported the
prevalence of HPV/EBV co‐infection in 11.9% of the combined oral
squamous cell carcinoma (OSCC) and oropharyngeal squamous cell
carcinoma (OPSCC) among a total of 1820 cases from different
studies.
96
In the case of OPSCC as the most common malignancy of
the head and neck, 15%–20% of carcinomas are detected as HPV/EBV
co‐infected.
96
However, there is a wide geographic variation of HPV
and EBV dual positivity. The highest HPV/EBV co‐infection rates were
34.7% for OSCC in Sweden and 23.4% for OPSCC in Poland.
96
Co‐
infection rates were observed to vary from 25% to 70% for SCC of the
tonsils and base of the tongue.
99
HPV/EBV co‐infection was also
reported in asymptomatic HPV
+
people,
83
and especially in oro-
pharynx, anorectum, and urethra of men who have sex with men
(MSM).
90
Moreover, EBV shedding was significantly correlated with
the prevalence and persistence of anal HR‐HPVs infection among HIV
+
MSM.
100
It seems likely to be a co‐factor for development of anal and
penile cancers in these people.
101–103
Furthermore, co‐infection with
HPV and EBV in oral leukoplakia can be associated with severe
dysplastic changes.
84
Numerous studies reported the HR‐HPVs/EBV
co‐existence ranging from 27.8% to 100% in HPV‐related cervical
cancer, and the potential cooperation of EBV as a co‐factor in this
cancer.
82,83,104
Additionally, a published meta‐analysis in 2018
demonstrated that co‐infection with HPV increases the risk of cervical
cancer in EBV
+
women up to four‐fold.
105
Precancerous cervical
lesions were associated with a two‐fold increase in EBV
+
women
compared to EBV
‐
women.
83
Furthermore, a few studies reported the
HPV/EBV co‐presence in other epithelial cancers such as breast
cancer, prostate cancer, and nasopharyngeal carcinomas.
106
Figure 1
indicates a hypothetical model of HR‐HPVs/EBV cooperation for the
development of cancer. The frequent co‐detection of these two
oncogenic viruses in different types of cancers suggests their
cooperation in driving malignancy through different complementary
mechanisms that will be described in the next section.
8.2.1 |HPV promotes EBV entry, latency and lytic
cycle activation
The in vitro and in vivo studies suggested that complement
receptor type 2 or CD21 (expressed variably in epithelial cells and
detected mainly in B cells) is responsible for attachment and entry
of EBV.
104,107
Dysplastic changes in oral epithelial cells are
significantly dependent on CD21 expression level that is higher in
EBV and HPV‐infected cases compared to HPV
−
/EBV
−
ones.
98
C3d is also another component of the complement system that is
widely expressed in the cervix and can bind to EBV. This
attachment may also protect the virus from complement‐
mediated lysis, and makes the cervical epithelium more sensitive
to various oncogenic stimuli.
106
In addition to CD21, the Ephrin
receptor A2 is the epithelial EBV receptor that is overexpressed
in HPV‐related cervical neoplasia (CN) compared to normal
cervical tissue.
96
These findings imply that HPV may help EBV
entrance into epithelial cells and increase the levels of proteins
involved in this process.
98
On the other hand, HPV infection and
its E6 and E7 oncogenes may play roles in the establishment of
latent EBV infection and reduction of EBV replication by changing
gene expression in EBV.
98
The HPV E7 can degrade the Rb, which
can stimulate cell cycle progression independent of p16 inhibition
of cyclin D/cyclin‐dependent kinase complexes. This process
recapitulates the events required to establish EBV latency in
epithelial cells.
8
DNA damage and overexpression of cyclin D1
and human telomerase reverse transcriptase (hTERT) in HPV‐
infected cells can promote the establishment of EBV latency. It
also increases cell susceptibility to EBV latency which is a crucial
first step in the development of EBV‐driven cancer.
96,98
Further-
more, the HPV E6 and E7 oncogenes can stimulate the expression
of an EBV immediate‐early lytic gene named as BZLF1 (BamHI Z
fragment leftward open reading frame 1), which favors the
increased EBV genome maintenance and production of EBV lytic
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genes with oncogenic features.
107
It is interesting to note that
thepresenceofEBVincreasesrateoftheHPV‐16 and ‐18
integrations into the host genome. The reports showed that EBV
infection can promote the integration of HPV16 DNA up to
seven‐fold.
98,103
It is important to consider that EBV can
permanently change gene expression even after a transient
infection, and the absence of the virus does not necessarily
indicate that it has not played a role in cancer development.
104
8.2.2 |HPV/EBV co‐infection mediates immune
evasion, suppression, and modulation
Both HPV and EBV show a large variety of evasion strategies that
interfere with innate and adaptive host immune responses.
8
The
evasion strategies by HPV may generateafavorableenvironment
for EBV secondary infection, and conversely.
104,107
Persistent
HPV infection can inhibit the expression of TLRs such as TLR2,
TLR3, TLR7, TLR8, and TLR9.
96
Furthermore, EBV disrupts TLR
sensing by suppressing the expression of TLR2 through the
proteins expressed by lytic genes such as BGLF5 and BPLF1.
Interfering with TLR9 sensing is also conducted through LMP‐1‐
mediated NF‐κB activation.
96,98
Thus, synergistic effects of HPV
and EBV on downregulating TLRs disrupt the innate immune
recognition of the virus, and facilitate infection.
36
Moreover, HPV
and LMP‐mediated NF‐κB activation can induce chronic inflam-
mation in HPV/EBV co‐infected organ sites.
108
While the
inflammation is aimed at generating a lethal environment for
pathogens, it paradoxically plays a major role in development of
EBV and HPV‐induced malignancies by generating reactive
oxygen species (ROS), releasing growth factors and cytokines,
and causing DNA damage and alterations in critical cell path-
ways.
109
Inflammatory factors and ROS were found to be more
highly expressed in HPV/EBV co‐infection compared to mono‐
FIGURE 1 A hypothetical model of high‐risk (HR)‐human papillomavirus (HPVs)/Epstein–Barr virus (EBV) cooperation for the development
of cancer: HPV genome integration and concomitant amplification of E6/E7 induce genome instability by the degradation of tumor repressors
p53 and Rb; E6/E7 oncoproteins inhibit the antiviral immune responses and induce immune evasion; E6/E7 oncoproteins induce BZLF1
expression, favoring the expression of EBV lytic genes such as BamHI‐A rightward frame 1 (BARF1) and BCRF1. E6/E7 oncoproteins also
enhance EBV latency; HPV E6/E7 and EBV latent membrane proteins‐1/BARF1 oncoproteins increase cell immortalization and cell proliferation;
BARF1 and BCRF1 inhibit the antiviral immune responses and induce immune evasion; and HR‐HPV infection induces CD21 (CR2), which, in
turn, promotes EBV entrance. Purple shapes symbolize HR‐HPV oncoproteins, and yellow shapes represent EBV proteins. The figure was
created by BioRender.com.
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infection.
109,110
Downstream impacts of activating NF‐κBand
signal transducers and activators of transcription 3 (STAT3)
increased additional pro‐inflammatory mediators leading to
inducing mutations, altering signaling pathways, and
promoting cell proliferation and survival, all of which contribute
to cancer development.
79
ROS can also inhibit the immune
response by disrupting T‐cell receptor signaling and suppressing
cytokine production. It was also proven to develop radio
resistance in cancer cells, thus hindering the efficacy of
treatment.
98
As the HPV E2, E5, and especially E6 proteins
suppress the interferon regulatory factor signaling and reduce
IFN‐αand IFN‐βproduction, the HR‐HPVs E6 and E7 oncopro-
teins stimulate the BZLF1 expression in EBV that have an
additional effect on decreasing IFNs type 1 production.
111
Similarly, the EBV BRLF1 and BARF1 proteins inhibit both the
synthesis and release of IFN‐α. BARF1 also downregulates other
human cytokines such as IL‐8andIL‐1αthat are related to
antitumor immune responses.
108,112
EBV also expresses a viral IL‐
10 (vIL‐10) as a protein homolog encoded by BCRF‐1genethat
causes local suppression in the cellular immune responses to
HPV‐transformed cells.
108
The vIL‐10 inhibits IFN‐γ,IL‐2, IL‐6,
TNF‐α,andgranulocyte‐macrophage colony‐stimulating factor
(GM‐CSF) production by CD4
+
T lymphocytes and monocytes
resulting in immune evasion of infected epithelial cells.
104
vIL‐10
impairs monocyte maturation and host natural defense system
against viral infections.
113
IL‐10inducedbyHPVE2,E6,andE7
proteins and vIL‐10 activate Janus kinase/STAT3 cascade that
leads to reduction of TNF‐α,IL‐6, and IL‐1βexpression
interfering with the NF‐κB signaling pathway with increased
tumorigenic and metastatic ability and epithelial‐mesenchymal
transition (EMT).
111,114
HPV E6 also interferes with the produc-
tion of other pro‐inflammatory cytokines and chemokines such as
TNF‐αand GM‐CSF as well as IL‐18, IL‐1βthat are associated
with an increased risk of developing cervical cancer.
114
Thus, the
interaction and cooperation between HPV and EBV proteins
impair host natural antiviral defense system, and produce a
chronic inflammatory microenvironment leading to carcinogene-
sis and tumor progression.
8.2.3 |HPV/EBV co‐infection mediates genome
instability and cell proliferation
Long‐term expression of EBNA‐1 and LMP‐1 in EBV‐infected cells
increased the ROS levels leading to DNA damage and oxidative
stress, and subsequently cell immortalization and malignant transfor-
mation.
110
Similarly, exposure of HPV‐infected cells to ROS increased
the levels of E6 and E7 proteins which could interfere with the
normal function of tumor suppressor p53 and Rb proteins.
109
LMP‐1
is the most important EBV immunomodulatory oncoprotein that
enhances the effects of E6 and E7 proteins on p53 and Rb
disruption.
98
It was reported that combination of EBV LMP‐1 and
HPV16 E6 proteins leads to a decrease in the components of DNA
damage response (DDR) including p27, Rb, and p53.
115
EBNA‐1 also
has an important role in EBV persistency and maintaining the
EBV genome latently. It decreases p53 and increases EMT and
angiogenesis.
115,116
LMP‐1 also induces downregulation of
E‐cadherin expression and also regulates some transcription factors
related to cell motility in collaboration with LMP‐2A.
110,117
More-
over, E6 and E7 oncoproteins upregulate the expression of EMT
markers such as N‐cadherin, fibronectin, and vimentin that increase
cell migration and invasiveness.
115
In addition, LMP‐1‐mediated
NF‐κB activation induces the expression of DNA binding 1 (Id‐1)
inhibitors which negatively regulates tumor suppressor p16 thus
increasing cell replication. It also induces cell immortalization by
upregulation of the Bcl‐2 oncogene and promotion of telomerase
activity via hTERT.
115,116
Al‐Thawadi et al. found an association
between the LMP‐1/E6 co‐expression and upregulation of the Id‐1in
cervical cancer.
111
LMP‐1 mediates activation in cancer pathways
such as phosphoinositide 3‐Kinase/Akt (PI3K/AKT), extracellular
signal‐regulated kinase (ERK), and c‐Jun N‐terminal kinase, which
leads to an increased cell growth, survival, and motility.
118
LMP‐1/E6
co‐expression also promotes cell survival by increasing the check-
point kinase 1, PI3K/AKT, mitogen‐activated protein kinase (MAPK),
and NF‐κB signaling pathways in the HPV/EBV co‐infection
cases.
98,115
Thus, co‐infection of HPV and EBV cooperatively
expands dysregulation of shared oncogenic pathways.
115
According
to some reports, the expression levels of antiapoptotic proteins such
as survivin and Bcl‐2 were significantly higher in the HPV/EBV co‐
infected cases than in noninfected ones.
110,117
Actually, the expres-
sion levels of E6 and E7 proteins have a direct association with
survivin and Bcl‐2 expression levels. Also, a direct association was
found between the expression levels of LMP‐1 and survivin.
110
Thus,
the expression of EBNA‐1, LMPs, and HR‐HPVs E6 in HPV/EBV co‐
infection promotes cell proliferation, resistance to apoptosis, and
anchorage‐independent growth associated with more aggressive
malignant tumors in cancer, and suggests a synergism between HPV
and EBV.
98
8.3 |Co‐infection of HPV with HIV
HIV is a member of the retroviridae family, and the etiological agent
of acquired immunodeficiency syndrome (AIDS).
119
HIV shows
tropism for several cell types including monocytes, dendritic cells,
and epithelial cells; however, its primary target is the depletion of
CD4
+
T lymphocytes through different mechanisms.
120,121
A strong
relationship was observed between genital HPV infection and the risk
of HIV acquisition.
122
Although most HPV infections will spontane-
ously be resolved, but their considerable rates will persist leading to
an increased risk of anogenital dysplasia especially in patients
infected with HIV. HIV and HPV co‐infection is common among
people living with HIV (PLWH).
78
Co‐infection with HPV and HIV
showed that cervical cancer is the most common AIDS‐defining
neoplasm in women. HIV changes the natural history of HPV
infection with decreased regression rates and more rapid progression
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to high‐grade and invasive lesions.
123
Although molecular interac-
tions between these two viruses were not completely understood;
but several mechanisms were proposed for interaction of both
viruses with the immune system.
8.3.1 |Viral–viral interaction
HPV infection of the cervix may enhance HIV infection
through induction of immune and inflammatory‐related protein
production.
124
The identification of HIV within macrophages under-
scores their significance as a crucial reservoir and a possible avenue
for HPV–HIV interaction. Furthermore, the interplay between viral
proteins could also play a role in this interaction.
124
HIV‐1 proteins
can directly lead to tumor growth by interfering with cellular
functions. For instance, HIV‐1 proteins such as Tat can interact with
the RB2/p130 tumor suppressor gene product and thus increase cell
proliferation.
125
The HIV‐Tat protein was known to facilitate cell‐
cycle advancement and decrease the presence of cell‐cycle suppres-
sors.
126
Dolei et al. revealed that exposure to Tat protein led to a
dose‐dependent rise in the expression of E1 and L1 genes.
127
Meanwhile, Vernon et al. demonstrated that the HIV‐1 tat protein
enhanced E2‐dependent HPV‐16 transcription.
128
Furthermore, the
expression of the HIV rev gene in epithelial cells enabled the
expression of L1 protein in undifferentiated basal keratinocytes.
Generally, the activation of both early and late HPV genes may
account for the increased virulence of HPV in the milieu of HIV
infection. For instance, HIV viral protein R (Vpr) facilitates the
infection of macrophages, and also disrupts the G2/M check‐point
with induction of apoptosis that is potentiated by HPV‐16 E6.
123
Toy
et al. suggested that Vpr may be useful as a cytostatic agent in
treatment.
129
Not only HPV may increase the susceptibility to HIV
infection, but also progression of HIV infection may be facilitated by
simultaneous HPV infection. Luque et al. showed the correlation of
active HPV infection with high HIV plasma RNA levels.
130
Moreover,
the HPV‐induced inflammatory cytokines especially IL‐6 cytokine
may stimulate HIV p24 expression in monocytes by binding to the
CAAT/enhancer binding protein B followed by activation of a
cascade of acute phase reactants and cytokines.
123
HIV/HPV co‐infection was related to an increased risk of
progression of CIN to cervical cancer. The results suggested that
co‐infection of HPV and HIV led to a significant increase in the
vascular endothelial growth factor A, p27, and Elf‐1 expression
compared to HPV
+
/HIV
−
(i.e., single HPV infection) infection that
could facilitate viral persistence and invasive tumor development.
124
Also, expression of RANTES in HIV/HPV co‐infection influenced the
development of CIN leading to the progression to cervical cancer.
Indeed, cervices from HIV‐positive patients exhibited HIV‐Nef
protein in the cells mainly around blood vessels, and a decreased
expression of cyclooxygenase‐1 (COX‐1) and TGFbRI, while RANTES
was highly expressed in the HIV/HPV and HPV‐infected patients
compared to controls.
131
Moreover, HIV‐1 infection increased the
levels of COX‐2 and systemic prostaglandin E2 in women with
cervical HPV suggesting a positive correlation with plasma HIV‐1
RNA levels.
132
The host immune response to HPV is mediated by
T‐lymphocytes.
133
This response may increase the risk of HIV since
T lymphocytes are primary target cells for HIV, and are upregulated in
HPV‐infected cervical tissues.
3
For instance, the IL‐1βcytokine
directly acts on T‐lymphocyte expansion and differentiation in vivo to
induce protective immunity against microbes and autoimmune
inflammation. Increased levels of IL‐1βwhich activates HIV
promoter
134
were detected in HPV‐associated abnormal cervical
cytology.
135
8.3.2 |Relationship between the CD4 lymphocyte
count and HPV infection
Although low CD4 lymphocyte count is related to a higher
prevalence of HPV; but however, the correlation of the CD4
lymphocyte count with CIN or cervical dysplasia is still
controversial.
78,136,137
It was reported that lower CD4 counts
increased the risk of vulvar dysplasia.
138
In general, immuno-
suppression and more advanced stages of HIV infection enhanced
the risk of HPV infection. Several studies showed an increased
risk for HPV infection in PLWH with a large CD4 depletion (i.e.,
CD4 counts <200 cells/μL).
78
High HPV load was related to a 10‐fold
increased risk of CIN among HIV‐positivewomenwithsevere
immunosuppression compared to women with higher CD4
+
counts.
139
Across‐sectional study in China reported an increased risk for anal HPV
infection in PLWH with CD4 counts <200 cells/μL. Moreover, a CD4
lymphocyte count <350 cells/μL was also related to an increased risk for
anal infection.
140
Similarly, a cross‐sectional study in Spain reported a
lower CD4 lymphocyte count among MSM with an HPV infection.
141
Several observational studies also showed an increased risk for cervical
infection in PLWH with a baseline CD4 lymphocyte count of <100 cells/
μL.
142,143
On the other hand, HIV‐positive women in Africa showed
higher viral load for combined alpha‐9HPVspeciescomparedto
HIV‐negative women. Moreover, HIV‐positivewomenwithCD4counts
>350/μL had significantly lower viral loads for alpha‐7HPVspeciesthan
HIV‐positivewomenwithCD4≤350/μL, but low CD4 count was not
significantly associated with increased viral load for other HPV
species.
144
8.3.3 |Relationship between antiretroviral therapy
(ART) and HPV
ART provides a normal life span to PLWH by maintaining an adequate
immune status along with the virological suppression of HIV. Several
studies showed the relationship between ART and the prevalence of
HPV. Different researchers reported a lower prevalence of cervix
HPV infection in PLWH receiving ART compared to untreated
patients.
145
In addition, a longer duration of ART among women was
associated with a lower prevalence of HR‐HPV infection in Kenya
146
suggesting higher immune control and clearance of HPV infection in
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the cervix.
145
Lower progression risk from low‐grade squamous
intraepithelial lesions to high‐grade squamous intraepithelial
lesions was reported among women who used ART.
147
In contrast,
another study reported that ART had a protective effect against
CIN2
+
but not against invasive carcinoma.
148
Several studies
indicated a lower prevalence of high‐grade anal dysplasia in patients
receiving ART than in ART‐naïve patients.
149,150
HR‐HPV‐positive
women showed higher circulating levels of T cells expressing
activation/exhaustion markers (CD38, programmed cell death protein
1, CTLA‐4, B‐and T‐lymphocyte attenuator, and CD160), Tregs, and
myeloid subsets expressing corresponding ligands (PDL1, PDL2,
CD86, CD40, herpesvirus entry mediator) than HR‐HPV negative
women. In ART‐suppressed HIV‐infected women with HPV co‐
infection, the levels of T cell (i.e., CD4
+
T cell) and myeloid cell
activation/exhaustion were associated with the presence of HR‐HPV
genotypes.
151
It was also reported that the cellular immunity induced
by the bivalent or quadrivalent vaccine in PLWH was importantly
similar to that in people without HIV.
152
However, a stronger
humoral immune response was detected in patients receiving a
bivalent vaccine compared to those receiving a quadrivalent
vaccine.
153
However, HPV vaccination in HIV‐positive individuals
seems to be a good idea, but its efficacy remains unproven.
154
8.3.4 |HPV genotypes found among co‐infection
with HIV
Several HPV genotypes were found among HPV and HIV‐co‐infected
people. HPV16 was the most common oncogenic virus in cervical
cancer among HIV‐negative and also HIV‐positive women.
155–157
However, HPV16 is responsible for a smaller proportion of invasive
cancers in HIV‐infected women indicating that immune‐compromise
does not further increase its oncogenic potential. However, other
genotypes (e.g., HPV types 18, 45, and 35) were also observed
among cervical cancer specimens
158–160
that can be linked to
HIV.
159,161
For example, the most prevalent HPV types were HPV‐
56 and HPV‐16 in Brazilian patients,
136
and HPV‐52 and HPV‐58 in
Chinese patients.
162
Moreover, HPV genotyping from cervical
samples of HIV‐positive patients in São Paulo showed that HPV‐56
was the predominant genotype followed by HPV‐16, HPV‐81, HPV‐
62, and HPV‐83. HPV types 6, 18, 26, 33, 52, 59, 72, 74, 90, and 114
were also observed at lower rates in these samples, respectively.
136
However, immunodeficiency can likely contribute to an increased
susceptibility to other types of HPVs in HIV‐infected patients. The
interaction of HIV and nononcogenic HPV is unclear. It is possible
that immune suppression contributes to the development of warts
(large and problematic warts), especially in tobacco smokers.
163
Although ART may reduce the size and recurrence risk of warts,
but this is not consistent, and genetic factors may influence this
interaction.
164
More HPV types are present in warts of immunosup-
pressed women, but HPV‐6 and HPV‐11 types are the most reported
types.
154,163
8.3.5 |HPV‐related cancer and their interplay
with HIV
The International Agency for Research on Cancer classified both
HPV and HIV‐1 as carcinogens.
165
Indeed, HPV is a direct
carcinogen and HIV‐1 is an indirect carcinogen through immune
suppression.
165
PLWH are at a HR of developing HPV‐related
cancers. Indeed, HIV positivity was linked to an increased
prevalence of cervical HPV infection and CIN.
166
Treatment of
CIN in HIV‐positivewomenfailsmoreoftenthaninHIV‐negative
women. In contrast, highly active antiretroviral therapy (HAART)
showedaprotectiveeffectontherecurrenceofCIN.
167
Gilles
et al. reported higher recurrence rates after treatment of CIN in
HIV‐positive women, and protection from recurrence after a
good viral response to HAART.
168
Moreover, high prevalence of
anal HPV infection, anal precancerous lesions, and anal cancer
in HIV‐positive individuals were reported in men and
women.
165,167,169,170
Other HPV‐related cancers such as OPC have
also been linked to HIV infection.
170
The HIV‐infected people
showed higher rates of OPC than HIV‐uninfected people.
165
Massad et al. studied the prevalence of genital warts and vulvar
intraepithelial neoplasia in HIV
+
and HIV
−
individuals, and showed
that the prevalence of warts was higher in HIV
+
than in HIV
−
subjects.
163
8.4 |HPV co‐infection with other viruses from
different families
Some studies reported the co‐presence of HPV and CMV in both
cancerous and noncancerous cervical samples.
82,171
CMV has also
been observed in cervical cancer samples with an impact on
increasing the integrated or mixed HPV‐16 genome up to six‐
fold.
171
It was hypothesized that the expression of immediate‐early
genes such as IE1 and IE2 in CMV activates other viral and cellular
genes in infected cells.
171
In fact, CMV infection can serve as a
transformation‐initiating factor in development of cervical cancer
according to hit‐and‐run theory. Thus, CMV infection may increase
the susceptibility to subsequent HPV infections and the risk of
carcinogenesis.
172
Possible cooperation of HPV and HHV‐6 was
previously reported in development of intraepithelial cervical
lesions.
173
Moreover, HHV‐8, also called Kaposi's sarcoma‐
associated herpes virus was transmitted during oral, vaginal, and
anal sex, and associated with several malignancies.
174
Few studies
reported HHV‐8/HPV co‐infection in immunocompromised patients
and cervical cancer up to 25%.
83,174,175
Based on the studies
conducted so far, the induction of chronic inflammation by HHV8
may contribute to development of a tumor‐promoting micro-
environment through production of IL‐6, IL‐8, macrophage migration
inhibitory factor, and different chemokines.
83,175,176
Moreover,
several studies have suggested the potential role of oncogenic
polyomaviruses particularly BK virus, JC virus, and Merkel Cell
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Polyomavirus in development of HPV‐associated malignancies such
as cervical and oral cancer.
177–180
These viruses infect epithelial cells
in a latent state and have a large T antigen that can block the
functionality of p53 and Rb family members in the cell leading to
tumor development.
8
Additionally, human T lymphotropic virus type
1 (HTLV‐1) is a sexually transmitted pathogen that has shared
transmission routes with HPV.
181
The studies showed that HTLV‐1
infection is associated with a higher prevalence of HPV acquisition,
particularly HR types. However, there is limited evidence on the
impact of HTLV‐1/HPV co‐infection in the development of cervical
cancer.
182,183
According to some studies, the prevalence of HIV,
HCV, and Treponema pallidum (causative organism of syphilis) was
relatively higher in HPV
+
patients than in the controls which showed
the increased possibility for the incidence of blood‐borne infectious
diseases among HPV‐infected individuals.
184,185
Similarly, higher
prevalence of Torque teno virus in HPV
+
patients was reported in
some studies that can be attributed to the same mode of
transmission and stimulation of the immune system by HPV
infection.
186,187
Thus, further research is needed to fully understand
the impact of co‐infection of HPV with other viruses on the
development of HPV‐related malignancies.
9|MICROBIOME AND HPV
A robust and healthy human microbiome plays a crucial role in
protecting the host from a broad range of foreign pathogens and
diseases.
188
It reduces inflammation and allows normal mucosal
function.
79
Conversely, dysbiosis (imbalance) of the microbiome has
been linked to chronic inflammation and the pathogenesis of mucosal
diseases.
189
It has profound effects on epithelial surface integrity,
mucosal secretion, and immune regulation.
188
As mentioned above,
in the context of HPV‐related cancers, viral infection serves as a
necessary agent but inadequate cause of cancer development.
37
Co‐
factors such as the immune response to viral infection, the host
microbiome health, or other acquired infectious agents play
additional roles in carcinogenesis.
97
The microbiome is an important
contributor to chronic mucosal inflammation, thus changes in its
composition by overgrowth or undergrowth of different bacterial
populations in multiple organ sites have been associated with
progression to HPV‐associated dysplasia.
79
It was proven that
bacterial shifts in the microbiome or co‐infection with other bacterial
pathogens in the organ affected by HPV can modulate viral
proliferation and infection.
97
Co‐infection/co‐presence of some
bacteria (either as part of the normal microbiome or as causative
agents of infections) with HPV can be assessed by DNA‐based or
serology tests. To better understand the bacterial‐viral interactions
involved in the initiation, development, and progression of HPV‐
related cancers, it may be useful to compare the microbiome of
healthy individuals with HPV‐infected patients.
78
The HPV, micro-
biome, and bacterial co‐infections are described in the development
of HPV‐related diseases in the next sections.
9.1 |Microbiome and HPV‐related cervical cancer
The relationship between HPV and the cervicovaginal microbiome
has widely been studied in recent years. Cervicovaginal mucosa acts
as a protective barrier against pathogens entering the upper part of
the female sexual tract. However, it is often compromised by
pathogen spreading and dysbiosis.
190
In cases of HPV infection,
inflammation of the cervix can act as a co‐factor for severe lesions.
Prolonged inflammation exposes the tissue to ongoing genotoxic
effects, leading to different forms of cancers.
191
Chronic inflamma-
tion can also accelerate the development of cervical cancer as well as
the initial alterations caused by HR‐HPVs.
192,193
Multiple studies
have proven that women with a specific cervicovaginal microbiota
composition may be more likely to acquire HPV or to show a faster
progression to CN.
194,195
Additional antigenic stimuli in the concur-
rent bacterial infection change the immunological responses, and
decrease the clearance of HPV.
185
In general, different cell stresses
such as high vaginal pH, production of nitrosamines by anaerobic
bacteria, and secretion of pro‐inflammatory cytokines such as
interleukins (IL‐1β,IL‐6, and IL‐8) in cervicovaginal dysbiosis enhance
the risk of mutation, and the oncogenic potential of HPV.
193,196–199
9.1.1 |BV and HPV
Multiple studies showed that the cervicovaginal microbiome of women
with persistent HPV infection is characterized by a high abundance of
anaerobic species from different genera.
188
An overgrowth of some
commensal bacteria was reported including Pseudomonas, Brevibacter-
ium, Peptostreptococcus, Delftia, Anaerococcus tetradius, Atopobium,
Shuttleworhia satelles, Megasphaera elsdenii, Fusobacteria,andSneathia
spp. with a decrease in Lactobacillus spp.population.
200–202
Further-
more, changing in microbial diversity as a result of BV was more
pronounced in HPV‐infected women.
188
BV is associated with major
changes in the vaginal environment by chronic inflammation because of
reduced levels of anti‐inflammatory molecule secretory leukocyte
protease inhibitor. It also induces epithelial barrier disruption by
producing epithelial‐lining‐degrading enzymes that help HPV en-
trance.
203
In addition, the production of IL‐1βand IL‐10 in BV impairs
cytotoxic T‐cell response and promotes HPV persistence and cervical
dysplasia.
193,195
Some reports suggested that lipopolysaccharide from
anaerobic bacteria in BV can interfere with tumor suppressors (e.g., p53
and E‐cadherin) which are also targeted by HPV oncoproteins.
97
Comparative genomic analysis of several studies showed that Gardner-
ella vaginalis,
195,204
Mycoplasma spp.,
196,205,206
and Ureaplasma urealy-
ticum
195,206–209
are the causal bacteria of BV that have a high
association with severe cervical lesions. These bacteria have been
identified as the main co‐factors of HPVs.
193,196
Other lower genital
tract infections including aerobic vaginitis and desquamative inflamma-
tory vaginitis are more common in HPV
+
women.
210
These infections
caninduceinflammationwithanincreaseinvaginalleukocytesandIL‐
1βand IL‐6 levels leading to a progressive CIN.
210,211
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9.1.2 |Bacterial sexually transmitted infections
(STIs) and HPV
Studies have also identified a possible association between STIs and
HPV infection.
210
The imbalance in the resident microbiota increases
susceptibility to upper genital tract infections and bacterial STIs
demonstrated the correlation of Gemella that have a significant
association with HPV infection by mucosal barrier disruption.
212
Neisseria gonorrhea (NG), Mycoplasma spp., and Chlamydia trachoma-
tis are the main bacterial STIs that provide an ideal niche for HPV
persistence and CN development.
195,197,200
They can interact with
HPV to develop HPV‐related dysplasia lesions in the cervix or the
anus by causing further localized inflammation.
213–215
The Myco-
plasmataceae family consists of two genera, Mycoplasma and
Ureaplasma, and is reported as the most significant differential
cervicovaginal bacteria between normal and precancerous cervical
cytology.
210,216
Mycoplasma hominis and Mycoplasma genitalium/HIV
co‐infection are prevalent in women. Also, these HIV
+
women are
mostly infected with multiple HPV genotypes like HPV‐16 and HPV‐
56.
196,217
Mycoplasmataceae represents a family of intracellular
bacteria with persistent infection that makes a cytokine‐mediated
inflammatory environment. Inflammation diminishes the microvilli in
cervical epithelial cells which favors virus entrance, persistence, and
HPV‐associated dysplasia.
218
They enhance carcinogenesis by
expressing proteins that can change biological mechanisms such as
programmed cell death and cellular metabolism.
97
According to some
reports, NG also increases the risk of cell transformation indepen-
dently, or in conjunction with HPV.
97
NG may interact with HPV by
dysregulation of multiple cellular signaling pathways and inducing
DNA double‐strand breaks (DSBs). It enhances the expression of pro‐
inflammatory cytokines and cyclin‐dependent kinase inhibitors p21
and p27, and decreases p53 expression.
97,219
Moreover, Trichomonas
vaginalis as a protozoan parasite STI causes micro‐lesions in the
cervical epithelium, and reduces the vaginal protective mucus layer
leading to the spread of HPV infection into the basal layer of the
cervical epithelium.
212
It also can increase the risk of cervical cancer
by developing an inflammatory environment through production of
nitric oxide (NO) by neutrophils in the cervix, which enhances DNA
damage, growth of abnormal cells, HPV entrance, and persistence.
220
TV infection can overexpress viral tumorigenesis which helps
activation of cancer‐causing pathways.
191
On the other hand, CT
has received more research interest as the most important pathogen
associated with HPV infection compared to other cervicovaginal
bacterial agents. Figure 2indicates the effects of C. trachomatis
infection and microbiome dysbiosis with HR‐HPVs in cancer
development. Therefore, we will further discuss its effects on the
increased risk of HPV‐driven cervical abnormalities.
9.2 |HPV/C. trachomatis co‐infection
C. trachomatis is a gram‐negative intracellular bacterium and the most
common bacterial STI among various sexually transmitted agents in
young people.
221
Although it is frequently asymptomatic, genital CT
infection in women has been associated with several severe diseases
including tubal factor infertility, pelvic inflammatory disease, chronic
pelvic pain, ectopic pregnancy, venereal lymphogranuloma, uterine
cervical lesions, newborn pneumonia, trachoma, and conjunctivi-
tis.
194,222,223
The connection between CT infection and HPV retention
was studied in various regions of the world.
213,224–227
These studies
suggested that CT is more prevalent in women who are infected with
HPV than in those who are not, so it makes HPV as a risk factor for
CT infection, and conversely.
224,225
Furthermore, several studies
demonstrated an association between HPV/CT co‐infection and
developing abnormal cervical cytology and dysplasia.
213,226,227
The
HPV and CT DNAs can be detected in approximately 99% of cervical
cancer cases.
228,229
There is a mutual benefit in HPV/CT co‐infection.
Indeed, CT affects the cervical microenvironment through promotion of
inflammatory conditions, and allows HPV penetration into the epithelial
cells. HPV also helps CT to spread and multiply by reduction of cell‐
mediated immunity.
228,230–232
Dysregulation of metabolic signaling and
immune responses, chronic inflammation, epithelial barrier breach,
uncontrolled cellular proliferation and apoptosis, genome instability, and
angiogenesis activation are different processes that appear to be crucial
in HPV/CT co‐infection and CN progression.
194
In the next sections, we
will review some mechanisms of HPV/CT co‐infection that may evoke
cervical cancer.
9.2.1 |HPV/CT co‐infection and genome instability
The correlation between HPV and CT infections with cervical tissue
transformation is based on the steady presence of both pathogens
that interfere with the host cells detection and repairing
mechanisms.
233
Thus, HPV/CT co‐infection leads to tissue damage,
and reduces local regenerative capacity.
234
Various proteins ex-
pressed by CT can target different subcellular compartments such as
nucleus, endoplasmic reticulum, and mitochondria. These proteins
may have detrimental effects on essential biological functions leading
to cancer development.
235
The coexistence of DNA‐binding proteins
from both human and CT within the nucleus creates a competitive
environment that may disrupt the binding of normal human proteins
to DNA, and increase the risk of malignancy.
233,235
Some of these
proteins recruit direct DSBs as the most dangerous form of DNA
damage due to their unrepaired nature.
226,236,237
Furthermore, CT
suppresses DNA repair activity by recruiting DDR proteins like
Ataxia‐telangiectasia‐mutated (ATM) away from sites of DSBs.
238
ROS production also causes oxidative DSBs and senescence‐
associated heterochromatin foci by subverting the host histones in
CT infection.
228
Free radicals damage the DNA and DNA repair
factors, and prevent apoptosis resulting in genetic fragility.
236,237
In
contrast to CT, HPV E6, and E7 proteins stimulate ATM‐dependent
homologous recombination, and activate the mismatch repair (MMR)
system to maintain cellular and genome integrity, which is necessary
for viral replication.
236,237
In the case of HPV/CT co‐infection, CT
impedes the HPV‐induced MMR system at both the transcriptional
12 of 21
|
AKBARI ET AL.
and posttranslational levels.
239–241
It reduces the transcription of the
MMR‐related genes by degrading the transcriptional factor E2F1.
242
CT infection also can modulate the protein serine/threonine
phosphatase 2A signaling pathway to suppress ATM activation,
which prevents cell cycle arrest. This contributes to a deficient high‐
fidelity HR pathway, and creates a conducive environment for further
mutagenesis.
242
9.2.2 |HPV/CT co‐infection and cell proliferation
The replication and propagation of intracellular pathogens can be
limited by cell death process.
226
Thus, manipulation of cell survival
and death pathways by CT can cause further cellular transformation
in HPV‐infected individuals.
234
CT creates a vacuole surrounded by a
membrane named as “inclusion”in which it can replicate and be ready
to infect other cells.
239–241
Both CT infection and HPV/CT co‐
infection trigger the oncogenic MAPK pathway (Ras‐Raf‐MEK‐ERK)
that regulates diverse cellular functions including cell proliferation,
survival, differentiation, and migration, thus promoting cancer cell
growth.
243,244
CT was also reported to activate PI3K/AKT that
enhances cellular proliferation, and blocks cell apoptosis.
238
Addi-
tionally, CT manipulates intrinsic apoptotic pathways by degrading
the MDM2 protein and inducing expression of antiapoptotic proteins
like Mcl‐1.
234
It also creates mitotic spindle defects causing the
premature host cells to exit from mitosis without the right
corrections.
226
Furthermore, cytokine‐mediated inflammatory
responses caused by chlamydial infection lead to fibrosis, tissue
dysfunction, and EMT by deposition of extracellular matrix
proteins.
245
These processes increase infected cell motility and
invasiveness, and decrease cell senescence and apoptosis, thus
promoting tumor progression.
194
On the other hand, EMT inducers
such as TGF‐βdownregulate protective modulators, and upregulate
fibrogenic and oncogenic modulators including miRNAs and tran-
scription factors which are associated with cellular transformation
and neoplasia.
246
It was reported that CT causes cervical epithelial
neoplasm by increasing Ki67 expression and decreasing p53 levels
due to the overexpression of E6 and E7 proteins. Ki67 is a cell
proliferation marker of cervical epithelium that is associated with
lesion intensity, and can be overexpressed during HPV/CT
co‐infection.
247
Moreover, during CT persistent chronic infection, a
large quantity of 60‐kDa heat shock proteins (named as CHSP60‐1)
are produced that interfere with host apoptosis and cellular
senescence processes.
248
Concomitant presence of HPV oncopro-
teins during CHSP60‐1 expression may lead to survival of apoptotic
stimuli, uncontrolled proliferation, and finally neoplastic transforma-
tion. Thus, it can provide favorable conditions for HPV persistence
and proliferation of HPV‐infected cells.
224
FIGURE 2 Possible outcomes of high‐risk‐human papillomavirus (HPVs) co‐infection with a Chlamydia trachomatis. (A) Long‐term silent
chlamydia infection and microbiome dysbiosis can contribute to the inflammation via cytokines and chemokines secretion or bacterial
metabolites directly. C. trachomatis also induces cell proliferation and chromosomal instability by dysregulating cellular pathways; (B) HPV can
infect the cells through epithelial barrier disruption, and cause further cellular transformation and immune suppression; and (C) These immune
activities contribute to the inflammation and tumor microenvironment, and further influence the cancer development. The figure was created by
BioRender.com.
AKBARI ET AL.
|
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9.2.3 |HPV/CT co‐infection and immune response
The co‐infection of CT and HPV (especially the 16, 18, 31, 33, 53, and
56 genotypes) is considered the most important risk factor for the
development of cervical cancer.
228
During the initial stages of HPV
infection, LCs play a critical role in initiating the immune response
against the virus.
249
They present antigens to T cells, and help immune
system to recognize and eliminate the virus.
250
HPV infects the host cell
persistently by suppressing this process.
251
Lu et al. demonstrated that
decreasing antigen presentation ability of LCs and its density are
significantly higher in the HPV/CT co‐infection cases than those in HPV
and CT single infections. In addition, chlamydia protease‐like activity
factor causes more immune dysfunction and viral persistence by
reducing the expression of MHC‐II and co‐stimulatory molecules on LCs
in HPV/CT co‐infection.
251
Indeed, activation of PI3K/AKT and MAPK
signaling pathways by HPV/CT co‐infection can contribute to immune
evasion and promote viral progression.
243
Co‐infection also leads to a
decrease in the number of CD4
+
and CD8
+
T cells, further suppressing
the cellular immune response against HPV and potentially leading to the
development of CN.
251
As HPV uses several molecular strategies to
evade innate and adaptive immunity, thus inflammatory patterns are
uncommon in mono‐HPV infection.
228
Instead, HPV infection is
characterized by a high number of regulatory T‐cells and activated
Th2 cells. This immunosuppressive microenvironment (through macro-
phage type 2 induction and IL‐10expressionbyHPVE2,E6,andE7
proteins) can be enhanced by TGF‐βderived from bacteria, and creates
a positive feedback loop between microbiota and cytokine profile.
252
It
also suppresses cytotoxic functions that lead to T cell anergy and may
explain the increased acquisition rate of other pathogens such as
CT.
228,235
The cytokine profiles of HPV/CT cervical samples showed the
increased levels of pro‐inflammatory cytokines including IL‐1β,IL‐6, and
TNF‐α, and the reduced levels of anti‐inflammatory cytokines including
IL‐4andIL‐10 compared to single infections or uninfected controls. This
cytokine profile of HPV/CT co‐infected samples was associated with
the severity of cervical lesions.
253
Moreover, both infections increased
the TNF‐mediated immune response, but only CT specifically induced
the inflammatory responses of IL‐17 and NF‐κB.
250
CT could activate
the innate immune response through the TLR2 and TLR4 resulting in the
activation of NF‐κB.
228,249
NF‐κB then induced the synthesis of pro‐
inflammatory cytokines including IFN‐γ,IL‐6, IL‐8, IL‐10, and IL‐12 as
well as the recruitment of neutrophils/macrophages.
251
In addition, CT
infection increased the production of IL‐6andTGF‐βcytokines that are
often associated with tumor progression.
228,249
The expression of these
cytokines was further enhanced in the presence of HPV E6 and E7
oncogenes
226
indicating a synergistic effect of HPV and CT infections in
promoting cancer development.
9.3 |Microbiome and other HPV‐related cancers
The carcinogenic process induced by HPV has been extensively
studied in cervical cancer, but the findings have been extrapolated
to other HPV‐related cancers like HNSCC, based on similarities in
the epithelial cells.
188
The underlying conditions such as poor dental
status, especially in heavy alcohol consumers and/or smokers are
correlated with shifts in the oral microbiome.
97
Expression of NO
and pro‐inflammatory cytokines such as TNF‐α,IL‐1β,andIL‐6in
oral dysbiosis induce chronic inflammation and modulation of
immune response. This compromised immune system and inflam-
matory environment make the host more susceptible to HPV
infection.
254
Furthermore, production of toxins and carcinogenic
metabolites such as acetaldehyde in oral dysbiosis activate signaling
pathways that promote cell proliferation and survival and damage
the DNA of oral epithelial cells leading to an increased risk of HPV‐
associated malignancies.
80
According to some epidemiological
studies, the oral microbiome in HPV‐infected patients was enriched
in anaerobic bacterial families such as Prevotellaceae, Veillonellaceae,
Campylobacteraceae,andBacteroidetes.
255
Actinomycetaceae family
as a common agent in periodontal disease, and a risk factor for
HNSCC was also more abundant in HPV
+
patients.
79,255
Other
studies showed the association of Selenomonas spp., Haemophilus,
Fusobacterium naviforme, and STI pathogens (e.g., CT or NG) with
oral HPV infection.
79,256–258
Additionally, some reports demon-
strated the correlation of Gemella and Leuconostoc with HPV‐
positive OCC and OPC, and the association of Streptococcus
anginosus with progression of OPSCC.
80,188
On the other hand,
Selenomonas noxia, Actinomyces, Granulicatella, Oribacterium, Cam-
pylobacter genera,Veillonella dispar, Rothia mucilaginosa,and
Haemophilus parainfluenzae were reported more prevalent in HPV
+
OPC patients compared to HPV
−
OPC.
254
Thus, oral bacterial
infections may act as an adjuvant risk factor and facilitate HPV
carcinogenic processes in some HNSCCs by altering the gene
expression directly (through virulence factors) or indirectly (through
oxidative stress and inflammation).
79
There is limited evidence to
support the interaction of anal and penile microbiome with HPV
infection. Furthermore, research characterizing the microbiome of
other HPV‐driven dysplasia is relatively nonexistent. Regarding the
association between penile microbiota and HPV infection, Onywera
et al. reported higher relative abundances of BV‐related bacteria,
especially Prevotella, Peptinophilus,andDialister in HPV‐infected
menincontrasttomenwithCorynebacterium‐dominated penile
microbiota that are less likely to have HR‐HPVs.
259
10 |CONCLUSION
In conclusion, co‐infections play a significant role in HPV‐associated
diseases by influencing the dynamics of HPV infection and
subsequently disease progression. Different infectious agents espe-
cially viruses and bacteria can interact with HPV leading to
complicated outcomes. The intricate interplay of HPV with co‐
infecting agents in diverse human tissues, and its impact on
carcinogenesis and disease progression calls for continued research
to devise comprehensive preventive and therapeutic strategies,
ultimately improving the management of HPV‐related malignancies
and associated diseases. Understanding these interactions is crucial
14 of 21
|
AKBARI ET AL.
for comprehensive management and prevention strategies against
HPV‐associated diseases. Thus, further research is needed to
uncover the precise mechanisms underlying these co‐infections and
their implications for HPV‐related cancer development.
AUTHOR CONTRIBUTIONS
Elahe Akbari, Alireza Milani, and Masoud Seyedinkhorasani wrote the
original draft and designed the figures. Azam Bolhassani was
responsible for conceptualization, review, and editing. All authors
approved the final manuscript.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
All data are available in the manuscript.
ORCID
Azam Bolhassani http://orcid.org/0000-0001-7363-7406
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How to cite this article: Akbari E, Milani A, Seyedinkhorasani
M, Bolhassani A. HPV co‐infections with other pathogens in
cancer development: a comprehensive review. J Med Virol.
2023;95:e29236. doi:10.1002/jmv.29236
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