Curr HIV/AIDS Rep
DOI 10.1007/s11904-014-0254-4
HIV PATHOGENESIS AND TREATMENT (AL LANDAY, SECTION EDITOR)
Human Papillomavirus in the HIV-Infected Host: Epidemiology
and Pathogenesis in the Antiretroviral Era
Cristina Brickman & Joel M. Palefsky
# Springer Science+Business Media New York 2015
Abstract Human papillomavirus (HPV) infection is associat-
ed with essentially all cervical cancers, 80–90 % of anal can-
cers, and a high proportion of oropharyngeal, vaginal, penile,
and vulvar cancers. Malignancy is preceded by the develop-
ment of precancerous lesions termed high-grade squamous
intraepithelial lesions (HSIL). Men and women with human
immunodeficiency virus (HIV) infection are at high risk of
HPV-related malignancies. The incidence of anal cancer in
particular has markedly risen during the antiretroviral era
due to the increased longevity of patients with HIV and the
absence of anal malignancy screening programs. HIV infec-
tion may facilitate initial HPV infection by disrupting epithe-
lial cell tight junctions. Once infection is established, HIV
may promote HSIL development via the up-regulation of
HPV oncogene expression and impairment of the immune
response needed to clear the lesion. HIV-infected women
should be screened for cervical HSIL and cancer, and HIV-
infected men and women should be considered for anal
screening programs.
Keywords Human papillomavirus . Human
immunodeficiency virus . Cervical cancer . Anal cancer .
Antiretroviral therapy . Anal squamous intraepithelial
lesions . Cervical squamous intraepithelial lesions
This article is part of the Topical Collection on HIV Pathogenesis and
Treatment
C. Brickman (*) : J. M. Palefsky
University of California San Francisco, Box 0654 513, Parnassus
Ave, Medical Science Room 420E, San Francisco, CA 94143, USA
e-mail: Cristina.Brickman@ucsf.edu
J. M. Palefsky
e-mail: Joel.Palefsky@ucsf.edu
Introduction
Human papillomaviruses (HPV) are a family of small, non-
enveloped DNA viruses that infect epithelial cells [1]. Of the
approximately 40 types that infect the anogenital epithelium
and upper digestive tract, 15–20 are considered oncogenic or
“high risk” (hr-HPV) [2]. Persistent infection with hr-HPV
leads to the development of squamous intraepithelial lesions
(SIL) and, in some cases, high-grade SIL (HSIL), the cancer
precursor. Infection with hr-HPV is associated with 99.9 % of
cervical cancers, 80–90 % of anal cancers, and a high propor-
tion of oropharyngeal, vaginal, penile, and vulvar cancers [3].
Men and women with human immunodeficiency virus
(HIV) are at particularly high risk of HPV-related malignan-
cies [4–6]. Given the longevity gained from antiretroviral ther-
apy (ART) [7], the impact of HPV infection on HIV-infected
patients is of increasing concern. In this article, we review the
most recent epidemiologic data on the two most frequent
HPV-related malignancies in patients with HIV: cervical and
anal cancer as well as the prevalence and natural history of
HPV infection and SIL in the ART era. Finally, we examine
the molecular mechanisms through which HPV infection
leads to cancer and explore how HIV infection may facilitate
malignant transformation.
Epidemiology of Cervical and Anal Cancer in Men
and Women with HIV
Cervical Cancer
Essentially all cases of cervical cancer result from HPV infec-
tion. Of the high-risk types, HPV-16 is responsible for over
50 % of cases, while HPV-16 and HPV-18 in combination are
responsible for 70 % of cervical cancers worldwide [8]. There
are over 500,000 new cases and 250,000 deaths from cervical

cancer in the world each year despite the advent of effective
screening [9]. Cervical cancer often affects a younger popula-
tion compared with other HPV-associated malignancies; in the
USA, it is most frequently diagnosed among women ages 33–
44 years [10]. The burden of the disease falls disproportion-
ately in the developing world where widespread screening is
not available. In the USA, the incidence of cervical cancer is
7.8 per 100,000 women-years [10], whereas the incidence in
many areas of sub-Saharan Africa exceeds 40 per 100,000
women-years [9].
In addition to tobacco use, the risk factors for cervical can-
cer are those associated with sexual transmission of HPV:
early onset of sexual activity, multiple sexual partners, high-
risk sexual partners, history of sexually transmitted infections
other than HPV, and a history of vulvar of vaginal SIL or
cancer [11].
Infection with HIV has emerged as an important risk factor
for cervical cancer. In 1993, the Centers for Disease Control
added invasive cervical cancer to the list of AIDS-defining
malignancies, joining Kaposi’s sarcoma (KS) and non-
Hodgkin’s lymphoma (NHL). [12]. This decision was contro-
versial because only an increase in cervical SIL had been
demonstrated in HIV-infected women at the time [13]. Subse-
quently, several large cohorts from the USA and Europe
showed standardized incidence ratios (SIRs) ranging from
5–10 for cervical cancer for HIV-infected women compared
with the general population [4, 6, 14, 15••].
Data on the incidence of cervical cancer among HIV-
infected women in the developing world are more limited.
Linkage of 15,000 HIV-infected individuals from Kyadondo
County, Uganda, to the county’s cancer registry led to an
estimated cervical cancer incidence of 70 per 100,000
women-years and a SIR of 2.7 when compared with HIV-
uninfected women [16]. There are also several case-control
studies from sub-Saharan Africa and India in which patients
with cancer were screened for HIV and the odds ratios (ORs)
of exposure to HIV were calculated [17–19]. ORs ranged from
1.1 to 7.9, but these results have limited generalizability since
they were derived from specific treatment centers instead of
from representative cohorts or registries.
Although elevated, the SIRs for cervical cancer in HIV-
infected women are considerably lower than those observed
for NHL and KS. This is due to both a higher incidence of
NHL and KS than cervical cancer in HIV-infected women and
to a lower incidence of NHL and KS than cervical cancer in
HIV-uninfected women. The difference in SIR magnitude
raises the question as to how closely cervical cancer is truly
linked to immunosuppression. Additionally, while the risk of
KS and NHL is strongly linked to low CD4 counts, only some
cohorts identified an association between cervical cancer and
CD4 count [6, 20], while others did not [4, 14]. Interpretation
is further confounded by the heterogeneity of CD4 endpoints
(e.g., CD4 nadir versus current CD4) used in the studies.
Curr HIV/AIDS Rep
The effect of immune restoration with ART on cervical
cancer is also somewhat unclear. While the incidence of KS
and NHL dropped quickly after the introduction of ART [13],
the earliest post-ART data showed stable rates of cervical
cancer [6, 21, 22]. More recent studies from the French Hos-
pital Database on HIV and the US HIV/AIDS Cancer Match
Study point to a decrease in incidence [15••, 23]; however,
these data may also reflect changes in screening practices and/
or in the prevalence of modifiable risk factors such as tobacco
use.
Anal Cancer
Of the 80–90 % of anal squamous cell carcinomas associated
with HPV infection, 70 % are associated with HPV-16 infec-
tion alone [24, 25••]. The most recent US data show an age-
adjusted incidence of 1.8 cases of anal cancer per 100,000
person-years [10]. This incidence is highest in women and
among people ages 55 to 64 years. Although the incidence
of anal cancer remains low compared with other malignancies,
the incidence has steadily increased over the last several de-
cades (Fig. 1 [26]). In the USA, the incidence of anal cancer
has more than doubled since 1975 and continues to rise by
about 2.2 % per year for both genders [10]. Similar increases
have been noted in several European countries and in Austra-
lia [27–31].
Similar to cervical cancer, risk factors for anal cancer in-
clude tobacco and factors associated with sexual acquisition of
anal HPV infection. These include a history of multiple sexual
partners, genital warts, receptive anal intercourse, and, in the
case of women, a history of cervical, vaginal and/or vulvar
SIL, or cancer [32–35]. In addition, HIV infection and other
forms of acquired immunosuppression have emerged as
Fig. 1 Age-adjusted incidence rate of anal cancer by gender and year of
diagnosis in the USA. Reproduced from Modern Colposcopy: Textbook
and Atlas, 2012
Curr HIV/AIDS Rep
arguably the strongest risk factors for anal cancer. There is at
least a 10-fold increase in incidence among HIV-infected
women compared with HIV-uninfected women [4, 22, 36••,
37••], and a greater than 40-fold increase in HIV-infected men
who only have sex with women (MSW) compared with their
HIV-uninfected counterparts [36••, 37••]. MSM with HIV in-
fection are at highest overall risk of developing anal cancer.
The age-adjusted incidence in this group has been estimated to
be as high as 131 per 100,000 person-years [36••, 37••], thus
making anal cancer as common or more common than any
other malignancy in this population [10].
A low CD4 count nadir, particularly when present for a
prolonged time, is associated with risk of anal cancer in sev-
eral studies [4, 6, 36••]; one study also identified an associa-
tion between anal cancer and low CD4 count at time of cancer
diagnosis [38]. However, as in the case of cervical cancer, the
association between low CD4 count and anal cancer was not
found in all studies [39].
The elevated risk of anal cancer in HIV-infected men is
partly responsible for the rising incidence of anal cancer in
the US male population; excluding HIV-infected men, the
increase in anal cancer in the general population of men is
1.7 %, whereas the annual increase is 3.4 % when they are
included [40]. The contribution of HIV infection to the inci-
dence of anal cancer in the general population of women is not
as apparent, presumably due to the smaller number of HIV-
infected women in the USA [41] and to the lower incidence of
anal cancer in HIV-infected women compared with HIV-
infected men.
As with cervical cancer, the effect of ART on anal cancer is
unclear. There is convincing evidence that the incidence of
anal cancer in HIV-infected patients has increased markedly
in the post-ART area, although results vary on whether this
rate continues to rise [6, 23, 39] or has plateaued [22, 36••].
However, this finding is attributed in great part to the in-
creased longevity of patients on ART who now live long
enough to develop cancer.
Two recent studies have attempted to measure the effect of
ART on anal cancer while accounting for the increased lon-
gevity of patients. A case-control study nested within the
Swiss HIV Cohort Study used incidence density sampling
and matching to account for differences in follow-up time as
well as in age and time period of cancer diagnosis [42]. This
study found no association between the diagnosis of anal can-
cer and a history of (any) ART. However, it did not account for
the presence or absence of virologic suppression or the dura-
tion of ART exposure. The second study is a retrospective
cohort from the Veterans Affairs HIV cohort study that exam-
ined the role of effective ART over time by comparing the
incidence rate of anal cancer among men on ART with and
without suppressed HIV viral loads [43]. Men who main-
tained a suppressed viral load had a lower incidence of anal
cancer thus suggesting a protective role for ART.
Thus, while risk of HPV-related malignancies appears to be
related to the degree of immunosuppression, particularly as
measured by low CD4 nadir, there is little to support a protec-
tive effect from immune restoration by ART, and the burden of
disease remains elevated in HIV-infected individuals. While
cervical cancer incidence in HIV-infected women has de-
creased in the US and Europe, this is unlikely to be the case
in the developing world where screening is not widely avail-
able. In comparison, the incidence of anal cancer has dramat-
ically increased among HIV-infected individuals following
the advent of ART. This difference may partly reflect the ab-
sence of screening programs for anal cancer. Furthermore,
because cervical cancer affects younger patients, the incidence
of cervical cancer may be less affected by the increased lon-
gevity conferred by ART.
HPV Infection in the ART Era
There are two leading indicators of future risk of HPV-
associated malignancies: HPV infection and HSIL. Infection
with anogenital HPV is extremely common in the general
population; the lifetime risk is estimated to be 75–80 % among
all sexually active men and women [44]. Initial cervical HPV
infection occurs soon after sexual debut with prevalence
peaking approximately 10 years later, followed by a gradual
decline with increasing age [45]. While HPV infection of the
anal canal is also thought to follow sexual debut, prevalence
remains constant with increasing age [46, 47].
HPV infection is even more common among HIV-infected
men and women than in the general population. The preva-
lence of cervical HPV in HIV-infected women is at least twice
that of HIV-uninfected women with comparable sexual risk
behaviors [48–52]. While the prevalence of anal HPV in HIV-
uninfected MSM is reported at 57 % [46], studies of HIV-
infected MSM have shown a prevalence of more than 95 %,
often with multiple and high-risk types [53, 54]. The preva-
lence of anal HPV infection is as high as 79–90 % in HIV-
infected women and about 50 % in HIV-infected MSW
[54–56], compared with 27 % in HIV-uninfected women
[47] and 12 % in HIV-uninfected MSW [57]. The higher
prevalence is attributed to higher rates of both incident and
persistent infection [58•].
Initial studies failed to demonstrate a protective effect of
ART for either cervical [59, 60] or anal HPV infection [61].
However, these studies were relatively small, had short
follow-up intervals, and were conducted early in the ART
era when medication was less effective. More recently, several
large prospective cohorts indicate that prolonged HIV sup-
pression with ART can modestly decrease cervical HPV infec-
tion [62•, 63•, 64]. One European cohort that reported a lower
risk of persistent hr-HPV infection with ART had a low

magnitude of association (OR 1.109) [62•]. In North America,
HIV-infected women on ART were twice as likely to clear hr-
HPV infection and half as likely to develop new hr-HPV in-
fection compared with HIV-infected women who were not on
ART [63•, 64]. However, the overall impact of these results is
uncertain given the elevated prevalence of cervical HPV in-
fection in HIV-infected women. Likewise, a recent cross-
sectional study of HIV-infected MSM reported a protective
effect of ART against anal HPV infection [65], but the reduc-
tion was modest compared to the overall infectious burden
(e.g., risk of any anal HPV infection was 89 % for subjects
on ART and 100 % for subjects not on ART).
Prevalence and Natural History of Squamous
Intraepithelial Lesions in the ART Era
Classification of Squamous Intraepithelial Lesions
In 1988, the Bethesda System was proposed to classify the
distinct cytologic changes that result from HPV infection of
the epithelium [66]. This nomenclature aimed to reflect a mor-
phologic continuum in which lesions progressed from low-
grade dysplasia to progressively higher-grade disease and,
eventually, to invasive cancer. Low-grade lesions, including
condylomas, were termed low-grade squamous intraepithelial
lesion (LSIL) on cytology and cervical intraepithelial neopla-
sia grade 1 on histology. High-grade lesions were designated
high-grade squamous intraepithelial lesions (HSIL) on cytol-
ogy and cervical intraepithelial neoplasia grades 2 and 3 on
histology.
Fig. 2 Schematic representation
of the two-tiered system to
classify cytology and histology of
squamous intraepithelial lesions.
Cervical intraepithelial neoplasia
(CIN) grade 1, anal intraepithelial
neoplasia (AIN) grade 1, and
condylomas are termed low-grade
squamous intraepithelial lesions
(LSIL). CIN/AIN grades 2 and 3
are termed high-grade squamous
intraepithelial lesions (HSIL).
The new classification reflects the
distinct biology underlying LSIL
and HSIL. Adapted from
Blaustein’s Pathology of the
Female Genital Tract, 2002
Curr HIV/AIDS Rep
However, the majority of low-grade lesions in the cervix
are transient and do not progress to high-grade dysplasia, even
when infection occurs with high-risk types [2]. Women with
low-grade cervical dysplasia are not at increased risk for high-
grade dysplasia compared with women with negative colpos-
copy [34]. Because of this, HPV infection is increasingly
thought to progress via two distinct pathways, resulting in
either low-grade (benign) or high-grade (precancerous) le-
sions. To reflect the shift away from a model that is character-
ized by incrementally severe dysplasia, the Lower Anogenital
Squamous Terminology (LAST) Project [67••] of the College
of American Pathologists and the American Society for Col-
poscopy and Cervical Pathology have recommended calling
all low-grade lesions “LSIL” and all high-grade lesions
“HSIL”.
In this paradigm, LSIL reflects active HPV replication
while HSIL reflects HPV-induced transformation (Fig. 2
[68]). This classification has therapeutic implications, since
the majority of LSIL resolve within 1–2 years [69]. They are
not considered precancerous and do not need to be treated
whereas HSIL, particularly in the cervix, is sought and treated
to reduce the risk of progression to cancer. The LAST project
also recommended extending LSIL/HSIL terminology to his-
topathologic grading of disease in addition to cytology grad-
ing and using uniform terminology across all anogenital sites
where HPV infection may lead to disease.
The American College of Obstetricians and Gynecologists
recently updated their guidelines for screening and manage-
ment of cervical HSIL [70]. Although there are no formal
guidelines for anal cancer screening, screening for anal HSIL
and invasive anal cancer should be considered in high-risk
populations, particularly MSM. A proposed screening
Curr HIV/AIDS Rep
algorithm is presented in Fig. 3 [26]. We recommend delaying
screening age 25 in asymptomatic HIV-infected MSM given
the low incidence rates of anal cancer below 25 years.
HSIL in HIV-Infected Men and Women
Older studies showed that both cervical cytological and histo-
logical abnormalities are more common in HIV-infected wom-
en compared with HIV-uninfected women [49, 71, 72]. As in
the case of HPV infection, this effect is due to both higher
incidence and persistence of cervical abnormalities in HIV-
infected women [58•, 73].
Given the high rates of anal HPV infection in HIV-infected
men and women, it is unsurprising that anal HSIL is also
common in this group. This is particularly true among HIV-
infected MSM among whom prevalence is 50 % compared
with 25 % in HIV-uninfected MSM [74, 75]. The Women’s
Interagency HIV Study showed a prevalence of 9 and 1 % of
anal HSIL in HIV-positive and HIV-negative women, respec-
tively, compared with 5 and 1 % for cervical HSIL [76]. A
subsequent study reported a prevalence of 3 % for anal HSIL
among HIV-infected women in the USA [77]. This number,
however, was derived from cytology samples and likely un-
derestimates the true prevalence of anal HSIL given the lim-
ited sensitivity of this technique [26]. One study showed an
18 % prevalence of HSIL among HIV-positive MSW [56],
while there is a paucity of data on their HIV-negative
counterparts.
As with the data on cancer incidence, the evidence regard-
ing the effect of ART on HSIL is conflicting [78]. The natural
history of HSIL is difficult to follow since it is often treated
once it has been identified. More recently, a longitudinal study
Fig. 3 Anal cancer/HSIL
screening algorithm. ASC-US
atypical squamous cells of
undetermined significance, ASC-
H atypical squamous cells cannot
exclude high-grade squamous
intraepithelial lesion, CMT
combined modality therapy,
DARE digital anorectal
examination, EUA examination
under anesthesia, HRA high-
resolution anoscopy, HSIL high-
grade intraepithelial lesions, LSIL
low-grade squamous
intraepithelial lesions. Adapted
from Current Infectious Disease
Reports, 2010
that censored data after treatment of cervical SIL found that
women on ART had three times the hazard of experiencing
spontaneous cervical SIL regression [63•]. Similarly, a second
longitudinal study that adjusted for treatment of cervical SIL
noted that women on ART had twice the hazard of regression
of hr-HPV positive SIL detected by cytology [64]. In the anus,
a cross-sectional study of MSM showed that patients on ART
were half as likely to have anal SIL [65]. As in the case of
HPV infection, the moderate measures of association suggest
that the impact of ART on SIL will be limited among patients
for whom the baseline prevalence of disease is already high.
Furthermore, the only recent study to evaluate the effect of
ART on HSIL specifically (as opposed to SIL overall) found
that MSM on ART for >4 years were less likely to develop
anal HSIL (OR 0.28), but the results were not statistically
significant [79].
Recent guidelines recommend initiating ART as early as
possible after the diagnosis of HIV infection [80], and it is
possible that early ART initiation when CD4 levels are rela-
tively high will lead to reduced incidence of HSIL and cancer
compared with those who initiate ART later. Unfortunately,
the proportion of HIV-infected men and women who would
initiate ART under these guidelines is relatively small, and
even if early ART initiation is associated with a lower risk of
HPV-associated malignancies, the expected effect on the over-
all incidence of these cancers would likely be limited.
Progression of HSIL to Invasive Cancer
Once cervical HSIL is present, the risk of progression to cer-
vical cancer is high. This is known from a study conducted in
New Zealand in which treatment of cervical HSIL was

withheld [81•]. The risk of invasive cervical cancer was 20 %
at 5 years and up to 50 % at 30 years among women with
HSIL who did not receive excisional therapy. The study also
showed an average time of 10 to 15 years for progression of
HSIL to invasive cancer [82].
The time to progression from cervical HSIL to cancer in
HIV-infected women has not been determined since treatment
of HSIL is standard of care. However, time to progression to
cervical cancer may be shorter in HIV-infected women since
they are typically diagnosed at a younger age than HIV-
uninfected women [15••]. The rate of progression from anal
HSIL to invasive anal cancer has likewise not been directly
measured. However, data on HPV prevalence and anal cancer
incidence were used to indirectly measure this rate in MSM
and was estimated to be 1 in 377 patients per year in HIV-
infected MSM and 1 in 4196 patients per year in HIV-
uninfected MSM [83••]. Given the increased longevity
afforded by ART, there may be as high as a 10 % lifetime risk
of anal cancer. Progression from anal HSIL to anal cancer may
be faster among given the younger median age of anal cancer
diagnosis in HIV-infected men and women compared with the
general population [36••].
The estimated rates of progression for anal HSIL are nota-
bly lower than the risk of progression to cancer for cervical
HSIL (approximately 1 in 80 per year) [81•], thus highlighting
the observation that on a per-HPV infection basis, anal HPV
infection is less likely to lead to cancer than cervical HPV
infection. The reason for the higher susceptibility of the cervix
to malignant transformation compared with the anus is not
known, but may involve factors such as the hormonal milieu
and potentially the different microbiomes of the two sites.
HPV Pathogenesis and HIV-HPV Interactions
HPV Pathogenesis
Anogenital HPV types preferentially infect areas of metapla-
sia in both the cervix and the anus [2, 26]. These areas, re-
ferred to as the transformation zones, are sites where columnar
glandular epithelium is being replaced by stratified squamous
epithelium. To establish infection, the virus must first access
the basal cells of the epithelium, a process thought to occur at
sites of microtrauma [84]. It is postulated that the changes in
receptors, adhesion molecules, and inflammatory mediators
associated with metaplasia facilitate access of HPV to the
basal cell layer of the epithelium [85].
The HPV genome is composed of double-stranded circular
DNA that is approximately 8 kb long. The genome can be
divided into an early region, which codes for largely regula-
tory proteins termed E1, E2, E4, E5, E6, and E7, and a late
region, which codes for two structural capsid proteins termed
Curr HIV/AIDS Rep
L1 and L2 [86]. Between these two regions lies the long con-
trol region (LCR) or upstream regulatory region (URR). The
LCR is a noncoding portion of the genome that contains four
binding sites for E2 as well as for multiple transcription
factors.
Once in the basal layer, the viral genome is maintained as a
relatively quiescent episome. Protein expression and active
HPV replication will increase as infected cells migrate into
the suprabasal cell layers and undergo epithelial differentia-
tion. However, latently infected cells may persist within the
basal cell epithelium [87, 88].
Persistent hr-HPV infection may lead to the development
of HSIL and potentially cancer. The process involves the up-
regulation of the two key HPVoncogenes: E7 and E6 [84]. E7
binds to the proto-oncogene retinoblastoma (Rb). Among its
functions, Rb associates with the E2F family of transcription
factors, which is involved in cell cycle regulation. The binding
of E7 to Rb leads to the release of E2F allowing for cellular
entry into the S-phase of the cell cycle. Cells undergoing rep-
lication are associated with higher mutation rates than nondi-
viding cells. E6 binds and inactivates the tumor suppressor
protein p53, which induces DNA repair enzymes that repair
mutations that occur during DNA replication. p53 may also
induce apoptosis when there is substantial damage. Thus, the
oncogenic functions of E6 and E7 are complementary; E7
increases the rate of mutations by enhancing DNA replication,
while E6 allows these mutations to accumulate by disrupting
DNA repair and cell death.
The accumulation of mutations results in progressive ge-
nomic instability that can eventually lead to invasive cancer.
The different mutational pathways, or “mutational signatures,
” involved in this process are complex. Studies using ad-
vanced sequencing technologies to characterize the breadth
of genomic alterations are ongoing [89]. These data will help
delineate the steps involved in progression from HSIL to can-
cer and may provide the bases for targeted antineoplastic
therapies.
The regulatory processes that determine whether HPV in-
fection remains primarily replicative leading to LSIL or trans-
formative leading to HSIL and cancer are not fully under-
stood. One major determinant is the HPV type, since persis-
tent HPV 16 is much likelier to result in HSIL and cancer than
infection with low-risk HPV types as well as other high-risk
HPV types [2]. This may result from differences in the func-
tion and affinity of the HPV 16 E6 and E7 oncoproteins for
their cellular target proteins compared with those of other
HPV types [90].
Another mechanism associated with HSIL and carcinogen-
esis is the integration of HPV DNA into the cellular genome.
Integration generally disrupts the E2 gene, a transactivating
protein that binds E2 binding sites in the LCR and down-
regulates E6 and E7 expression when all four sites are occu-
pied. Hence, viral integration may result in the increased
Curr HIV/AIDS Rep
expression of E6 and E7 [91] and the development of HSIL.
However, the processes that regulate integration itself are
unknown.
Epigenetic changes are also being studied as mediators of
the transformation process [91]. These refer to genomic struc-
tural modifications that affect gene expression without altering
the underlying DNA sequencing. In cervical cancer speci-
mens, both DNA hypermethylation and enhanced histone
deacetylation inhibit the expression of tumor suppressor
genes. Cervical cancer is also associated with the aberrant
expression of micro-RNAs, small noncoding RNAs that reg-
ulate protein expression and that have been recently associated
with oncogenesis.
Mechanisms of HIV-HPV Interaction
While the risk of HPV-related malignancy is related to the
degree of immunosuppression, immune reconstitution with
ART does not have a clear effect on the incidence of HSIL
or its progression to invasive cancer. These findings support a
model where HIV facilitates initial infection and development
of precancerous lesions but is less involved in malignant trans-
formation once HSIL is present.
HIV may enable initial HPV infection through the disrup-
tion of epithelial tight junctions [92••]. HIV-infected immune
cells secrete the viral proteins tat (transactivator protein) and
gp120, both of which are known to disrupt epithelial tight
junctions and can be isolated from the mucosal environment
of HIV-infected individuals. A recent study showed that treat-
ment of mucosal epithelial tissue explants with tat and gp120
markedly increased the passage of HPV 16 pseudovirions to
the basal cell layer, where initial infection is established. tat
has also been shown in vitro to up-regulate E6 and E7 expres-
sion in HPV 16-positive human oral keratinocytes, suggesting
that tat also facilitates the development of HSIL lesions after
infection has been established.
Immune defects associated with HIV infection also contrib-
ute to HPV pathogenesis. Cell-mediated immunity plays a key
role in SIL regression, as evidenced by the infiltration of CD4+
T cells, CD8+ T cells, and macrophages that occurs prior to
spontaneous resolution of LSIL [93]. In humans, HIV infec-
tion results in the rapid and irreversible loss of CD4+ T cells
from the gut mucosa [94]. It is postulated that a similar mu-
cosal dysfunction occurs in the anogenital epithelium and hin-
ders the spontaneous resolution of HPV-associated lesions.
Interestingly, a high proportion of HIV-infected women
being followed longitudinally who have a newly detected cer-
vical HPV infection report no new sexual exposures since
their prior visit [58•]. Given the absence of sexual activity, this
suggests an additional mechanism through which immune
defects promote HPV pathogenesis: the reactivation of previ-
ously latent HPV. This theory is supported by two studies that
found markedly increased rates of cervical HPV infection im-
mediately following HIV acquisition [95•, 96•].
Although ART has no clear effect on the natural history of
HSIL, the younger age at which HIV-infected patients are
diagnosed with cervical and anal cancer makes it impossible
to completely exclude an effect of HIV in accelerating the
progression from HSIL to malignancy. This effect, if present,
would likely consist of mechanisms independent of ART and
may involve ongoing attenuation of cell-mediated immunity
or to the presence of persistent inflammation [97].
Conclusions
The impact of HPV in HIV-infected patients can only be ex-
pected to increase given the magnitude of the HIV epidemic,
the increased longevity of patients with HIV, and the absence
of a discernible effect of ART on the incidence of either anal or
cervical cancer. This highlights the need for public health
measures to curtail the effects of the HPV epidemic in HIV-
infected patients.
Compliance with Ethics Guidelines
Conflict of Interest Cristina Brickman declares that she has no conflict
of interest.
Joel Palefsky reports grants, travel support, and board membership
from Merck & Co., Inc.; grants from Hologic; and stocks from Aura
Biosciences, and he is a consultant for Qiagen.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
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tify and perform HPV testing on anal cancer specimens. 90% of
anal cancers are associated with HPV-infection, primarily HPV-16.
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32. Daling JR et al. Correlates of homosexual behavior and the inci-
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35. Saleem AM et al. Risk of anal cancer in a cohort with human
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36.•• Piketty C et al. Incidence of HIV-related anal cancer remains in-
creased despite long-term combined antiretroviral treatment: results
from the French hospital database on HIV. J Clin Oncol.
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marizes recent incidence trends for anal cancer in HIV-infected
patients.
37.•• Silverberg MJ et al. Risk of anal cancer in HIV-infected and HIV-
uninfected individuals in North America. Clin Infect Dis.
2012;54(7):1026–34. Recent incidence rates of anal cancer among
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40. Shiels MS et al. Impact of the HIV epidemic on the incidence rates
of anal cancer in the United States. J Natl Cancer Inst.
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41. Prevention, C.f.D.C.a. HIV surveillance report, 2011. 2013
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43. Chiao EY et al. The impact of HIV viral control on the incidence of
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45. Dunne EF et al. Prevalence of HPV infection among females in the
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46. Chin-Hong PV et al. Age-Specific prevalence of anal human papil-
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sex with men: the EXPLORE study. J Infect Dis. 2004;190(12):
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47. Hernandez BY et al. Anal human papillomavirus infection in wom-
en and its relationship with cervical infection. Cancer Epidemiol
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48. Silverberg MJ et al. The impact of HIV infection and immunodefi-
ciency on human papillomavirus type 6 or 11 infection and on
genital warts. Sex Transm Dis. 2002;29(8):427–35.
49. Massad LS et al. Prevalence and predictors of squamous cell abnor-
malities in Papanicolaou smears from women infected with HIV-1.
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Syndr. 1999;21(1):33–41.
50. Palefsky JM et al. Cervicovaginal human papillomavirus infection
in human immunodeficiency virus-1 (HIV)-positive and high-risk
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51. Jamieson DJ et al. Characterization of genital human papillomavi-
rus infection in women who have or who are at risk of having HIV
infection. Am J Obstet Gynecol. 2002;186(1):21–7.
52. Watts DH et al. Effects of bacterial vaginosis and other genital
infections on the natural history of human papillomavirus infection
in HIV-1-infected and high-risk HIV-1-uninfected women. J Infect
Dis. 2005;191(7):1129–39.
53. de Pokomandy A et al. Prevalence, clearance, and incidence of anal
human papillomavirus infection in HIV-infected men: the
HIPVIRG cohort study. J Infect Dis. 2009;199(7):965–73.
54. Conley L et al. Factors associated with prevalent abnormal anal
cytology in a large cohort of HIV-infected adults in the United
States. J Infect Dis. 2010;202(10):1567–76.
55. Palefsky JM et al. Prevalence and risk factors for anal human pap-
illomavirus infection in human immunodeficiency virus (HIV)-pos-
itive and high-risk HIV-negative women. J Infect Dis. 2001;183(3):
383–91.
56. Piketty C et al. High prevalence of anal human papillomavirus
infection and anal cancer precursors among HIV-infected persons
in the absence of anal intercourse. Ann Intern Med. 2003;138(6):
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57. Nyitray AG et al. Prevalence of and risk factors for anal human
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58.• Strickler HD et al. Natural history and possible reactivation of hu-
man papillomavirus in human immunodeficiency virus-positive
women. J Natl Cancer Inst. 2005;97(8):577–86. First study to show
that newly detected HPV infection occurs in celibate women, sug-
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59. Lillo FB et al. Human papillomavirus infection and associated cer-
vical disease in human immunodeficiency virus-infected women:
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60. Del Mistro A et al. Antiretroviral therapy and the clinical evolution
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with extended follow-up time. Shows very limited effect of ART in
decreasing the risk of persistent cervical hr-HPV infection.
63.• Blitz S et al. Evaluation of HIV and highly active antiretroviral
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Additional recent large cohort of HIV-infected women with
extended follow-up time. Shows limited effect of ART in promoting
regression of SIL.
64. Minkoff H et al. Influence of adherent and effective antiretroviral
therapy use on human papillomavirus infection and squamous
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66. The 1988 Bethesda System for reporting cervical/vaginal cytolog-
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72. Chirenje ZM et al. Association of cervical SIL and HIV-1 infection
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75. Chin-Hong PV et al. Comparison of patient- and clinician-collected
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92.•• Tugizov SM et al. HIV-associated disruption of mucosal epithelium
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HIV-derived tat and gp120 disrupt epithelial tight-cell junctions
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93. van der Burg SH, Palefsky JM. Human immunodeficiency virus
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96.• Wang C et al. Rapid rise in detection of human papillomavirus
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HIV leads to the reactivation of previously latent HPV.
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