Immediate precircumcision HIV viral loads were available for 70% (68/97) of HIV-infected individuals. Epithelial inflammation was present in 44.1% (15/34) of men with log viral loads above the median of 4.5 log10 cps/ml, and 14.7% (5/34) in those with viral loads below the median (Fisher exact test, P = 0.02).
Foreskin inflammation was associated with both HIV and HSV-2 infections in unadjusted analyses (Table 1), and the highest prevalence of inflammation in the foreskin epithelium and stroma was observed in coinfection with HIV and HSV-2, in the adjusted analysis (Table 2). The inflammation was primarily mononuclear, suggesting local immune activation and cellular recruitment, possibly resulting from chronic viral infection . The greater prevalence of foreskin inflammation in HIV-positive men with higher HIV viral loads supports this contention. In situ replication of T cells could play a role in presence or severity of inflammation. However, replication in the skin would most likely occur at sites of preexisting host response, where secreted cytokines lead to T-cell recruitment and activation .
Coinfection with HSV-2 and HIV was associated with the highest prevalence of inflammatory changes (Table 1), which may influence the infectivity of HIV-positive men. This is consistent with epidemiologic studies suggesting that HSV-2 enhances HIV genital shedding [23,24] and that coinfection potentiates the clinical severity and infectiousness of the two viruses . These findings may provide insight into the potential mechanisms by which the foreskin may facilitate HIV transmission.
The presence of smegma on preoperative examination was associated with inflammation and may be a surrogate marker of poor genital hygiene. However, the role of smegma in foreskin inflammation is unclear. It may be a result of local inflammation or may contribute to the inflammation we observed. Poor hygiene (as measured by daily washing of the genitalia or washing after sex) has been associated with an increased risk of HIV and STI acquisition in some [34–36], but not all studies .
The major limitation of this study is that of necessity it was cross-sectional because foreskin tissues were only available at time of surgery. However, the viral infections must have preceded the observed inflammatory changes. Furthermore, our study does not include data regarding other STIs at the time of circumcision, and because infection with HIV and/or HSV-2 is associated with a higher risk for other STIs, the latter could contribute to genital inflammation. A strength of this study is the sample size and the fact that the participants did not have medical indication for circumcision. Previous studies of foreskin immunology had small sample sizes, little or no epidemiologic data or only individuals needing medically indicated circumcision due to phimosis or other genitourologic problems [19,38–41]. Moreover, these prior studies did not include HIV+ men and could not assess infection with HSV-2.
Our findings suggest that HIV and HSV-2 are associated with dramatically enhanced foreskin inflammation.
The trials were funded by the National Institutes of Health (NIH) (U1AI51171), the Bill & Melinda Gates Foundation (22006.02), and the Fogarty International Center (5D43TW001508 and D43TW00015). This study was supported in part by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIH. Authors include Andrew D. Redd, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. K.E.J., M.E.S., C.S.R. designed the study. K.E.J. conducted the study, gathered the data, performed the analysis and wrote the article. M.E.S. and M.A.D. interpreted the histopathology of the foreskin tissues. R.H.G. and V.S. assisted with the statistical analysis. A.A.R.T. performed the HSV-2 serologic assays. R.H.Q., M.W., D.S., G.K. designed and conducted the circumcision studies. R.H.G., J.Z., A.D.R., A.A.R.T., T.C.Q. assisted in writing the article.
We thank Dr Rajni Sharma, Department of Pathology, Johns Hopkins University, for her development of IHC protocols and staining and Alexander P. Rabkin for his assistance with tissue processing. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article. The authors wish to thank the circumcision trial study participants for their commitment and cooperation.
This work was presented in part at the joint meeting of the American Sexually Transmitted Disease Association/British Association for Sexual Health and Hygiene (ASTDA/BASHH), Brooklyn, NY, 2008 and published as an abstract in the meeting summary.
K.E.J. has received research funding support through a Bristol-Myers Squibb virology fellowship.
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