Penile Immune Activation and Risk of HIV Shedding: A Prospective Cohort Study

Eshan U. Patel, Allison R. Kirkpatrick, Mary Kate Grabowski, Godfrey Kigozi, Ronald H. Gray, Jessica L. Prodger, Andrew D. Redd, Fred Nalugoda, David Serwadda, Maria J. Wawer, Thomas C. Quinn, Aaron A.R. Tobian

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Genital immune activation is suspected to modulate local human immunodeficiency virus (HIV) RNA levels and the risk of sexual HIV transmission.

Methods: 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.

Findings: 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.

Interpretation: 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.

Original languageEnglish (US)
Pages (from-to)776-784
Number of pages9
JournalClinical infectious diseases : an official publication of the Infectious Diseases Society of America
Volume64
Issue number6
DOIs
StatePublished - Mar 15 2017

Keywords

  • genital inflammation
  • human immunodeficiency virus (HIV)
  • immune activation
  • male circumcision
  • sexual transmission.

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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