title: Penile Immune Activation and Risk of HIV Shedding: A Prospective Cohort Study.
abstract: Genital immune activation is suspected to modulate local human immunodeficiency virus (HIV) RNA levels and the risk of sexual HIV transmission.
  
  
  
  A prospective, observational cohort study of 221 HIV-infected men undergoing male circumcision (MC) was conducted in Rakai, Uganda. Penile lavage samples collected from the coronal sulcus at baseline and 4 weekly visits after MC were assayed for pro-inflammatory cytokines and HIV RNA. The main analysis was limited to 175 men with detectable HIV plasma viral load (VL > 400 copies/mL; n = 808 visits). The primary exposures of interest were individual and total cytokine detection at the previous postoperative visit. Adjusted prevalence risk ratios (adjPRR) of detectable HIV shedding (VL > 40 copies/mL) were estimated by Poisson regression models with generalized estimating equations and robust variance estimators and included adjustment for plasma HIV VL.
  
  
  
  Among men with a detectable plasma VL, penile HIV shedding was detected at 136 visits (16.8%). Detectable interleukin (IL)-1β (adjPRR = 2.14; 95% confidence interval (CI) = 1.02-4.48), IL-6 (adjPRR = 2.24; 95% CI = 1.28-3.90), IL-8 (adjPRR = 2.42; 95% CI = 1.15-5.08), IL-10 (adjPRR = 2.51; 95% CI = 1.67-3.80), and IL-13 (adjPRR = 1.87; 95% CI = 1.15-3.03) were associated with penile HIV shedding at the subsequent visit. Men with 2-4 (adjPRR = 2.36; 95% CI = 1.08-5.14) and 5-7 (adjPRR = 3.00; 95% CI = 1.28-7.01) detectable cytokines had a greater likelihood of detectable penile HIV shedding at the subsequent visit, compared to men with ≤ 1 detectable cytokine. The total number of detectable cytokines was also associated with a higher penile log10 HIV VL at the subsequent visit among HIV shedders.
  
  
  
  Pro-inflammatory cytokine production had a dose-dependent and temporal association with penile HIV shedding, suggesting that genital immune activation may increase the risk of sexual HIV transmission by driving local HIV replication.
authors.affiliation: Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Baltimore, Maryland, USA.|Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Eshan U
authors.initials: EU
authors.lastname: Patel
authors.affiliation: Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Baltimore, Maryland, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Kirkpatrick
authors.affiliation: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.|Rakai Health Sciences Program, Entebbe, Uganda.
authors.forename: Mary Kate
authors.initials: MK
authors.lastname: Grabowski
authors.affiliation: Rakai Health Sciences Program, Entebbe, Uganda.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Kigozi
authors.affiliation: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.|Rakai Health Sciences Program, Entebbe, Uganda.
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Gray
authors.affiliation: Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Baltimore, Maryland, USA.|Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prodger
authors.affiliation: Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Baltimore, Maryland, USA.|Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Redd
authors.affiliation: Rakai Health Sciences Program, Entebbe, Uganda.
authors.forename: Fred
authors.initials: F
authors.lastname: Nalugoda
authors.affiliation: Rakai Health Sciences Program, Entebbe, Uganda.|Institute of Public Health, Makerere University, Kampala, Uganda.
authors.forename: David
authors.initials: D
authors.lastname: Serwadda
authors.affiliation: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.|Rakai Health Sciences Program, Entebbe, Uganda.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Baltimore, Maryland, USA.|Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.|Rakai Health Sciences Program, Entebbe, Uganda.|Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Quinn
authors.affiliation: Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Aaron A R
authors.initials: AA
authors.lastname: Tobian
mesh_terms: D000328:Adult; D015415:Biomarkers; D018791:CD4 Lymphocyte Count; D002944:Circumcision, Male; D060085:Coinfection; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000453:epidemiology / Q000276:immunology* / Q000635:transmission / Q000821:virology*; D006801:Humans; D007109:Immunity; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010413:Penis / Q000276:immunology*; D011446:Prospective Studies; D012725:Sexual Behavior; D014454:Uganda / Q000453:epidemiology; D019562:Viral Load; D017201:Virus Shedding; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: genital inflammation; human immunodeficiency virus (HIV); immune activation; male circumcision; sexual transmission.