title: HIV acquisition is associated with increased antimicrobial peptides and reduced HIV neutralizing IgA in the foreskin prepuce of uncircumcised men.
abstract: BACKGROUND
  The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition.
  
  
  METHODS
  To assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda.
  
  
  RESULTS
  Participants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted OR = 0.31; 95% CI, 0.16-0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11-0.39). Levels of the α-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten-fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 log(n) pg/mL, P = 0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 log(n) pg/mL, P = 0.0002 and 0.013).
  
  
  CONCLUSIONS
  This prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk.
authors.affiliation: Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Taha
authors.initials: T
authors.lastname: Hirbod
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Kong
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Godgrey
authors.initials: G
authors.lastname: Kigozi
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ndyanabo
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda; School of Public Health, College of Medicine, Makerere University, Kampala, Uganda.
authors.forename: David
authors.initials: D
authors.lastname: Serwadda
authors.affiliation: Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prodger
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Tobian
authors.affiliation: Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Fred
authors.initials: F
authors.lastname: Nalugoda
authors.affiliation: Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
authors.forename: Kamnoosh
authors.initials: K
authors.lastname: Shahabi
authors.affiliation: Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Rojas
authors.affiliation: Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
authors.affiliation: Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Broliden
authors.affiliation: Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.affiliation: Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Rakai Health Sciences Program, Kalisizo, Uganda.
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Gray
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D002944:Circumcision, Male; D052816:Foreskin / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D020010:Heterosexuality; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014454:Uganda; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D057134:Antibodies, Neutralizing; D007070:Immunoglobulin A