title: Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda.
abstract: Individual susceptibility to HIV is heterogeneous, but the biological mechanisms explaining differences are incompletely understood. We hypothesized that penile inflammation may increase HIV susceptibility in men by recruiting permissive CD4 T cells, and that male circumcision may decrease HIV susceptibility in part by reducing genital inflammation. We used multi-array technology to measure levels of seven cytokines in coronal sulcus (penile) swabs collected longitudinally from initially uncircumcised men enrolled in a randomized trial of circumcision in Rakai, Uganda. Coronal sulcus cytokine levels were compared between men who acquired HIV and controls who remained seronegative. Cytokines were also compared within men before and after circumcision, and correlated with CD4 T cells subsets in foreskin tissue. HIV acquisition was associated with detectable coronal sulcus Interleukin-8 (IL-8 aOR 2.26, 95%CI 1.04-6.40) and Monokine Induced by γ-interferon (MIG aOR 2.72, 95%CI 1.15-8.06) at the visit prior to seroconversion, and the odds of seroconversion increased with detection of multiple cytokines. Coronal sulcus chemokine levels were not correlated with those in the vagina of a man's female sex partner. The detection of IL-8 in swabs was significantly reduced 6 months after circumcision (PRR 0.59, 95%CI 0.44-0.87), and continued to decline for at least two years (PRR 0.29, 95%CI 0.16-0.54). Finally, prepuce IL-8 correlated with increased HIV target cell density in foreskin tissues, including highly susceptible CD4 T cells subsets, as well as with tissue neutrophil density. Together, these data suggest that penile inflammation increases HIV susceptibility and is reduced by circumcision.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Jessica L
authors.identifier: http://orcid.org/0000-0003-0805-4196
authors.initials: JL
authors.lastname: Prodger
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.|Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Gray
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Brett
authors.initials: B
authors.lastname: Shannon
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Kamnoosh
authors.initials: K
authors.lastname: Shahabi
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Kate
authors.initials: K
authors.lastname: Grabowski
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Kigozi
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Fred
authors.initials: F
authors.lastname: Nalugoda
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: David
authors.initials: D
authors.lastname: Serwadda
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.|Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Maria J
authors.identifier: http://orcid.org/0000-0002-3601-4469
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.|Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.|Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, Maryland.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Reynolds
authors.affiliation: Department of Environmental and Occupational Health, George Washington University, Washington, District of Columbia.|Translational Genomics Research Institute, Flagstaff, Arizona.
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Liu
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Aaron A R
authors.initials: AA
authors.lastname: Tobian
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Rupert
authors.identifier: http://orcid.org/0000-0002-1586-4093
authors.initials: R
authors.lastname: Kaul
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D018925:Chemokines / Q000032:analysis / Q000276:immunology; D002944:Circumcision, Male; D004198:Disease Susceptibility / Q000276:immunology / Q000821:virology; D052816:Foreskin / Q000276:immunology; D015658:HIV Infections / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000821:virology; D016209:Interleukin-8 / Q000276:immunology; D008163:Luminescent Measurements; D010413:Penis / Q000276:immunology / Q000601:surgery; D014454:Uganda
chemical_list: D018925:Chemokines; C508606:CXCL8 protein, human; D016209:Interleukin-8