title: The inner foreskin of healthy males at risk of HIV infection harbors epithelial CD4+ CCR5+ cells and has features of an inflamed epidermal barrier.
abstract: Male circumcision provides partial protection against multiple sexually transmitted infections (STIs), including HIV, but the mechanisms are not fully understood. To examine potential vulnerabilities in foreskin epithelial structure, we used Wilcoxon paired tests adjusted using the false discovery rate method to compare inner and outer foreskin samples from 20 healthy, sexually active Peruvian males who have sex with males or transgender females, ages 21-29, at elevated risk of HIV infection. No evidence of epithelial microtrauma was identified, as assessed by keratinocyte activation, fibronectin deposition, or parakeratosis. However, multiple suprabasal tight junction differences were identified: 1) inner foreskin stratum corneum was thinner than outer (p = 0.035); 2) claudin 1 had extended membrane-bound localization throughout inner epidermis stratum spinosum (p = 0.035); 3) membrane-bound claudin 4 was absent from inner foreskin stratum granulosum (p = 0.035); and 4) occludin had increased membrane deposition in inner foreskin stratum granulosum (p = 0.042) versus outer. Together, this suggests subclinical inflammation and paracellular transport modifications to the inner foreskin. A setting of inflammation was further supported by inner foreskin epithelial explant cultures secreting higher levels of GM-CSF (p = 0.029), IP-10 (p = 0.035) and RANTES (p = 0.022) than outer foreskin, and also containing an increased density of CCR5+ and CD4+ CCR5+ cells (p = 0.022). Inner foreskin dermis also secreted more RANTES than outer (p = 0.036), and had increased density of CCR5+ cells (p = 0.022). In conclusion, subclinical changes to the inner foreskin of sexually active males may support an inflammatory state, with availability of target cells for HIV infection and modifications to epidermal barriers, potentially explaining the benefits of circumcision for STI prevention.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Lemos
authors.affiliation: Asociación Civil Impacta Salud y Educación, Lima, Perú
authors.forename: Javier R
authors.initials: JR
authors.lastname: Lama
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Shelly T
authors.initials: ST
authors.lastname: Karuna
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Fong
authors.affiliation: US Naval Medical Research Unit 6 (NAMRU-6), Lima, Perú
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Montano
authors.affiliation: Asociación Civil Impacta Salud y Educación, Lima, Perú
authors.forename: Carmela
authors.initials: C
authors.lastname: Ganoza
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gottardo
authors.affiliation: Asociación Civil Impacta Salud y Educación, Lima, Perú
authors.forename: Jorge
authors.initials: J
authors.lastname: Sanchez
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
mesh_terms: D000328:Adult; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D002944:Circumcision, Male; D062445:Claudin-1 / Q000378:metabolism; D062506:Claudin-4 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004817:Epidermis / Q000473:pathology / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D052816:Foreskin / Q000378:metabolism* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015658:HIV Infections; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D062793:Occludin / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D063106:Transgender Persons
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; C568108:CLDN1 protein, human; C568157:CLDN4 protein, human; C114753:CXCL10 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D062445:Claudin-1; D062506:Claudin-4; D016207:Cytokines; D062793:Occludin; D019713:Receptors, CCR5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor