Topical Oestrogen Keratinises The Human Foreskin and May Help Prevent HIV Infection

Pask, Andrew J; McInnes, Kerry J.; Webb, David R.; Short, R. V.

doi:10.1371/journal.pone.0002308

Cited by 18 publications

(11 citation statements)

References 18 publications

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“…Filaggrin binds to keratin and helps keratin filaments aggregate in the superficial-most layers of the epidermis [8, 9]. This marker allowed us to visualize the stratum corneum of the epithelium, the equivalent of what has previously been defined as “keratin” [5, 6, 10]. This molecular definition of keratin based on filaggrin expression facilitated accurate measurement of the thickness of this layer and provided an alternative technique to evaluate foreskin keratin.…”

Section: Resultsmentioning

confidence: 99%

Keratinization of the adult male foreskin and implications for male circumcision

Dinh

McRaven

Kelley

et al. 2010

Aids

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Objective The theory that a more thinly keratinized inner foreskin leads to increased HIV-1 susceptibility has been based on relatively little published data. We sought to quantify the keratin thicknesses of the inner and outer foreskin to determine the plausibility of this hypothesis. Design We took repeated measurements of the keratin layer of 16 adult male foreskins to determine if differences existed between the inner and outer foreskin. Methods Adult foreskins were collected from consenting donors undergoing elective male circumcision for unknown medical indications in Chicago, IL. Specimens were processed, sectioned and stained for keratin using anti-filaggrin fluorescent antibodies. Slides stained with H&E were used as controls to compare to previously published studies using this method. Keratin layers were measured in a standardized fashion for each specimen. Results Comparing our fluorescence-based analysis to previously published immunohistochemical methods revealed that our method was highly accurate for measuring foreskin keratin thickness. There was significant heterogeneity in the keratin thickness of the inner and outer aspects of the male foreskin within and between the different donors. There was no significant difference between the inner and outer foreskin keratin thickness (25.37 ± 12.51 and 20.54 ± 12.51μm respectively, p=0.451). Conclusions We found no difference between the keratinization of the inner and outer aspects of the adult male foreskin. Keratin layers alone are unlikely to explain why uncircumcised men are at higher risk for HIV infection.

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Section: Resultsmentioning

confidence: 99%

Keratinization of the adult male foreskin and implications for male circumcision

Dinh

McRaven

Kelley

et al. 2010

Aids

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show abstract

“…Relevant to HIV‐1, the higher extent of outer foreskin keratinization has been suggested to provide a protective barrier against HIV‐1 transmission 44,52 . Surprisingly, only two previous studies have investigated the mechanism of foreskin HIV‐1 entry.…”

Section: The Foreskin Epithelium and Hiv‐1mentioning

confidence: 99%

HIV‐1 Transmission in the Male Genital Tract

Ganor

Bomsel

2010

American J Rep Immunol

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HIV-1 is mainly a sexually transmitted infection, and epithelial surfaces covering genital mucosa are the primary site of HIV-1 transmission. Although male circumcision was reported to reduce male acquisition of HIV-1 by 60%, the initial mechanisms of HIV-1 transmission in the male genitals remain elusive. We established two novel models of the adult human foreskin epithelium that allowed for polarized infection via the mucosal pole with either HIV-1-infected cells that are present in all secretions vectorizing HIV-1 or cell-free HIV-1. Efficient HIV-1 transmission occurs following 1 hr of polarized exposure of the inner, but not outer, foreskin to mononuclear cells highly infected with HIV-1, but not to cell-free virus. HIV-1-infected cells form viral synapses with apical foreskin keratinocytes, leading to polarized budding of HIV-1, which is rapidly internalized by Langerhans cells (LCs) in the inner foreskin. In turn, LCs form conjugates with T-cells, thereby transferring HIV-1. Seminal plasma from HIV-negative men mixed with cervico-vaginal secretions from HIV-positive women, which mimics the in-vivo mixture of these genital fluids during woman-to-man HIV-1 sexual transmission, decreases HIV-1 infection at the foreskin. Our results rationalize at the cellular level the apparent protective outcome of circumcision against HIV-1 acquisition by men.

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“…21 -23 Such a higher degree of foreskin keratinization has been suggested to provide a protective barrier against HIV-1 transmission. 22,24 Potential HIV-1 target cells expressing CD4, the principal receptor for HIV-1, and the coreceptor CCR5 are present in the inner and outer foreskin. 21 -23,25 -27 To date, only two published studies of foreskin infection with HIV-1 have evaluated the entry of high doses of cell-free HIV-1 inocula at time points of > 24 h. First, on polarized infection of agarose-sealed foreskin tissue explants, the inner foreskin appears susceptible to infection with R5, but not X4, cell-free HIV-1.…”

Section: Introductionmentioning

confidence: 99%

Within 1 h, HIV-1 uses viral synapses to enter efficiently the inner, but not outer, foreskin mucosa and engages Langerhans–T cell conjugates

et al. 2010

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Although circumcision reduces male acquisition of human immunodeficiency virus type-1 (HIV-1) by 60%, the initial mechanisms of HIV-1 transmission at the foreskin remain elusive. We have established two novel and complementary models of the human adult foreskin epithelium, namely, ex vivo foreskin explants and in vitro reconstructed immunocompetent foreskins. In these models, efficient HIV-1 transmission occurs after 1 h of polarized exposure of the inner, but not outer, foreskin to mononuclear cells highly infected with HIV-1, but not to cell-free virus. HIV-1-infected cells form viral synapses with apical foreskin keratinocytes, leading to polarized budding of HIV-1, which is rapidly internalized by Langerhans cells (LCs) in the inner foreskin. In turn, LCs migrate toward the epidermis-dermis interface to form conjugates with T cells, thereby transferring HIV-1. Seminal plasma mixed with cervicovaginal secretions inhibits HIV-1 translocation. This set of results rationalizes at the cellular level the apparent protective outcome of circumcision against HIV-1 acquisition by men.

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Topical Oestrogen Keratinises The Human Foreskin and May Help Prevent HIV Infection

Cited by 18 publications

References 18 publications

Keratinization of the adult male foreskin and implications for male circumcision

Keratinization of the adult male foreskin and implications for male circumcision

HIV‐1 Transmission in the Male Genital Tract

Within 1 h, HIV-1 uses viral synapses to enter efficiently the inner, but not outer, foreskin mucosa and engages Langerhans–T cell conjugates

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