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Jiy 505
Jiy 505
MAJOR ARTICLE
Beth Israel Deaconess Medical Center, Boston, and 5Division of Pediatric Infectious Diseases and Immunology, UMass Memorial Children’s Medical Center, Worcester,
Massachusetts
Background. Condylomata acuminata (anogenital warts [AGWs]) are prevalent in human immunodeficiency virus (HIV)–
Human papillomavirus (HPV) is one of the most prevalent sex- brought to medical attention until they cause discomfort, pru-
ually transmitted pathogens in humans; most sexually active ritus, or bleeding.
adults are infected with at least 1 strain of HPV during their AGWs are prevalent in groups at high risk for HIV acqui-
lifetime [1–3]. Of >100 known types of HPV, 13 are classified sition and in HIV-infected individuals. In seronegative men
as high risk (ie, cancer causing). Low-risk HPV strains 6 and 11 who have sex with men, the prevalence of low-risk HPV
are associated with the occurrence of condylomata acuminata infection associated with AGWs is about 20% [8, 9]. A recent
(anogenital warts [AGWs]), benign epithelial lesions that often meta-analysis showed that the prevalence of AGWs in HIV-
develop at sites that are vulnerable to abrasion or injury during uninfected populations at high risk for HIV acquisition in
sexual intercourse [4, 5]. Anal warts are observed primarily in sub-Saharan Africa (ie, female sex workers and men and
individuals who engage in receptive anal intercourse, but they women attending sexually transmitted disease [STD] clinics)
may also occur in men and women with no such history [6]. ranges from 2.4% to 14% [10]. HIV-infected men and women
Genital warts are usually found under the foreskin or on the have a higher prevalence of HPV infection, AGWs, and pre-
shaft of the penis in men and on the external genitalia/introitus malignant and malignant lesions, compared with age-matched
in women [7]. AGWs are often asymptomatic and may not be uninfected controls [11].
A number of recent studies have shown an increased risk of
HIV acquisition in individuals with HPV infection [12–17] and
those with AGWs [18, 19], and it has been speculated that HPV
may enhance HIV acquisition because of inflammation and
Received 7 May 2018; editorial decision 27 July 2018; accepted 16 August 2018; published
online August 20, 2018. an increased numbers of HIV target cells at the infection site
aJ. P. and Z. W. are co–first authors.
[20]. HPV clearance, rather than HPV infection, has also been
Correspondence: D. J. Anderson, PhD, Department of Obstetrics and Gynecology, 670 Albany
St, Ste 516, Boston University School of Medicine, Boston, MA 02118 (Deborah.Anderson@ implicated as a factor in HIV acquisition [17, 21, 22]. AGWs
BMC.org). could also be a site of enhanced HIV shedding and transmission
The Journal of Infectious Diseases® 2019;219:275–83 from HIV-infected individuals to uninfected partners; however,
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. studies to date have not associated HPV infection or AGWs
DOI: 10.1093/infdis/jiy505 with HIV transmission.
% Tissues w/Cells
2+
TZM-bl assay [35]. Biopsy specimens from AGWs and normal 60
3+
perianal tissue (control) were transported on ice to BUMC.
40 4+
Tissue specimens were cut into sections (2 mm × 2 mm ×
1 mm), and replicate pieces were transferred to 24-well tissue 20
C D
B C D
A B A B
C D C D
Figure 3. CD1a+ dendritic cells detected by immunohistologic staining (red) in Figure 5. CD68+ macrophages detected by immunohistologic staining (red) in
normal anogenital skin specimens (A) and anogenital wart specimens (B and C). A, normal anogenital skin specimens (A) and anogenital wart specimens (B–D). A,
Normal vulvar skin specimen demonstrating a few CD1a+ cells in the epidermis and Normal vulvar skin specimen with CD68+ cells located primarily in the dermis (20×
fewer in the dermis (20× original magnification). B, Vulvar wart specimen displaying original magnification). B, Vulvar wart specimen showing CD68+ cells infiltrating
hyperkeratosis and acanthosis with numerous CD1a+ cells in the epidermis (40× koilocytes in epidermis (40× original magnification). C, Penile wart specimen with
original magnification). C, Clitoral wart specimen with pronounced hyperkeratosis numerous CD68+ cells associated with accumulations of lymphocytes in the dermis
and numerous CD1a+ cells in the stratum corneum (SC) and stratum spinosum (40× (20× original magnification). D, Vulvar wart specimen showing an area of localized
original magnification). D, Penile wart specimen showing focal accumulations of CD68+ macrophage infiltration into the epidermis (20× original magnification). SC,
CD1a+ cells in the dermis (40× original magnification). stratum corneum.
CD1a+ DCs
Approximately half of the AGW cases had abundant (score, were concentrated in the upper epithelial layers (ie, the stratum
+++ or greater) CD1a+ DCs in the epidermis (Figure 1). In granulosum and stratum corneum; Figure 3C) or the stratum
many samples, these cells were dispersed throughout the width basalis. CD1a+ DCs were also consistently detected in the der-
of the stratum spinosum (Figure 3B), whereas in others they mis and/or dermal papillae in AGW samples. In a substantial
serostatus was not significant for any of the white blood cell of granulocytes or any of the HIV target cells in the epidermis.
counts (Table 1). There were no donor-matched tissue speci- However, all 3 HIV target cell types were often found associated
men pairs available from men with genital warts, but data were with CD8+ T cells in focal aggregates in the dermis layer.
compared for penile wart specimens from 5 subjects and normal
penile tissue specimens from 5 unrelated subjects. The epider- Infection of AGW and Control Specimens With HIV In Vitro
mal layer of male genital wart specimens had significantly higher Donor-matched samples of anal warts and normal anal epithe-
concentrations of CD1a+ (P = .004) and CD68+ (P = .009) cells lium were obtained from 9 HIV-negative men (89% were white;
(both P values were determined by the Mann-Whitney U test). age range, 20–29 years). All wart samples were anal intraepi-
thelial neoplasia grade 1–2 on pathologic review. One case was
Correlations Between HIV Target Cells, CD15+ Granulocytes, discarded because of contamination. Two of 8 AGW samples
and CD8+ T Cells in AGW Specimens versus 0 normal tissue samples showed definitive signs of HIV
Granulocyte concentrations were positively correlated infection, as evidenced by robust TZM-bl values (>1000 relative
with CD68+ cell numbers in the AGW epidermis (ρ = 0.54; light units on >2 days of culture) and p24 assay confirmation
P < .0001) but not with CD1a+ DCs or CD4+ lymphocytes. (Figure 6); because of the small sample size, these data were not
CD8+ T-cell concentrations were not correlated with numbers significant (P > .10).
RLU
100 BI-7 Control Skin
10
0.1
3 7 11 14
Days