title: Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda.
abstract: Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibility may be mediated by immune alterations in the genital mucosa. However, immune correlates of HIV exposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n=20) and unexposed control (n=57) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets from foreskin tissue were assessed by flow cytometry. HESN foreskins had elevated α-defensins (3,027 vs. 1,795 pg ml(-1), P=0.011) and HIV-neutralizing IgA (50.0 vs. 13.5% of men, P=0.019). Foreskin tissue from HESN men contained a higher density of CD3 T cells (151.9 vs. 69.9 cells mm(-2), P=0.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04% of CD4 T cells, P=0.007), and fewer produced tumor necrosis factor α (TNFα) (34.3 vs. 41.8% of CD4 T cells, P=0.037; 36.9 vs. 45.7% of CD8 T cells, P=0.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFα production, in combination with HIV-neutralizing IgA and α-defensins, may represent a protective immune milieu at a site of HIV exposure.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Prodger
authors.affiliation: Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Hirbod
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: G
authors.initials: G
authors.lastname: Kigozi
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: F
authors.initials: F
authors.lastname: Nalugoda
authors.affiliation: 1] Rakai Health Sciences Program, Kalisizo, Uganda [2] Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [3] Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Reynolds
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: R
authors.initials: R
authors.lastname: Galiwango
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Shahabi
authors.affiliation: 1] Rakai Health Sciences Program, Kalisizo, Uganda [2] Institute of Public Health, Makerere University, Kampala, Uganda.
authors.forename: D
authors.initials: D
authors.lastname: Serwadda
authors.affiliation: 1] Rakai Health Sciences Program, Kalisizo, Uganda [2] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: 1] Rakai Health Sciences Program, Kalisizo, Uganda [2] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Gray
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Kaul
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D052816:Foreskin / Q000276:immunology* / Q000821:virology; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D018023:HIV Seronegativity / Q000276:immunology; D006679:HIV Seropositivity / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007070:Immunoglobulin A / Q000276:immunology; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012725:Sexual Behavior; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014454:Uganda; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D015483:HIV Antibodies; D007070:Immunoglobulin A