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.
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.
1. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision
for reduction of HIV
infection risk: the ANRS 1265 Trial. PLoS Med 2005; 2:e298.
2. Bailey R, Moses S, Parker C, Agot K, Maclean I, Krieger JN, et al
. Male circumcision
prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet 2007; 369:643–656.
3. Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, et al
. Male circumcision
prevention in men in Rakai, Uganda
: a randomised trial. Lancet 2007; 369:657–666.
4. Wawer MJ, Kigozi G, Serwadda D, Makumbi F, Nalugoda F, Watya S, et al. Trial of male circumcision in HIV+ men, Rakai, Uganda: effects in HIV+ men and in women partners.
The 15th Annual Conference on Retroviruses and Opportunistic Infections; 2 April 2008. Boston, MA.
5. Tobian AA, Serwadda D, Quinn TC, Kigozi G, Gravitt PE, Laeyendecker O, et al
. Male circumcision
for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360:1298–1309.
6. Grosskurth H, Gray R, Hayes R, Mabey D, Wawer M. Control of sexually transmitted diseases for HIV
-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet 2000; 355:1981–1987.
7. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV
infection. Sex Transm Infect 1999; 75:3–17.
8. Stamm WE, Handsfield HH, Rompalo AM, Ashley RL, Roberts PL, Corey L. The association between genital ulcer disease and acquisition of HIV
infection in homosexual men. JAMA 1988; 260:1429–1433.
9. Plummer FA, Simonsen JN, Cameron DW, Ndinya-Achola JO, Kreiss JK, Gakinya MN, et al
. Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. J Infect Dis 1991; 163:233–239.
10. Laga M, Manoka A, Kivuvu M, Malele B, Tuliza M, Nzila N, et al
. Nonulcerative sexually transmitted diseases as risk factors for HIV
-1 transmission in women: results from a cohort study. AIDS 1993; 7:95–102.
11. Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2
-seropositive persons: a meta-analysis. J Infect Dis 2002; 185:45–52.
12. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV
acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20:73–83.
13. Reynolds SJ, Risbud AR, Shepherd ME, Zenilman JM, Brookmeyer RS, Paranjape RS, et al
. Recent herpes simplex virus type 2
infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis 2003; 187:1513–1521.
14. Koelle DM, Abbo H, Peck A, Ziegweid K, Corey L. Direct recovery of herpes simplex virus (HSV)-specific T lymphocyte clones from recurrent genital HSV-2 lesions. J Infect Dis 1994; 169:956–961.
15. Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV
-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004; 35:435–445.
16. Castle PE, Hillier SL, Rabe LK, Hildesheim A, Herrero R, Bratti MC, et al
. An association of cervical inflammation
with high-grade cervical neoplasia in women infected with oncogenic human papillomavirus (HPV). Cancer Epidemiol Biomarkers Prev 2001; 10:1021–1027.
17. Kovacic M, Katki HA, Kreimer A, Sherman ME. Epidemiologic analysis of histologic cervical inflammation
: relationship to human papillomavirus infections. Human Pathol 2008; 39:1088–1095.
18. Bhoopat L, Eiangleng L, Rugpao S, Frankel SS, Weissman D, Lekawanvijit S, et al
. In vivo identification of Langerhans and related dendritic cells infected with HIV
-1 subtype E in vaginal mucosa of asymptomatic patients. Mod Pathol 2001; 14:1263–1269.
19. Patterson BK, Landay A, Siegel JN, Flener Z, Pessis D, Chaviano A, Bailey RC. Susceptibility to human immunodeficiency virus-1 infection of human foreskin
and cervical tissue grown in explant culture. Am J Pathol 2002; 161:867–873.
20. Gamiel JL, Tobian AA, Laeyendecker OB, Reynolds SJ, Morrow RA, Serwadda D, et al
. Improved performance of enzyme-linked immunosorbent assays and the effect of human immunodeficiency virus coinfection on the serologic detection of herpes simplex virus type 2
in Rakai, Uganda
. Clin Vaccine Immunol 2008; 15:888–890.
21. Janeway CA, Travers P. Immunobiology: the immune system in health and disease
. New York: Garland; 1997. pp. 9:13–9:20.
22. Luster AD. Chemokines – chemotactic cytokines that mediate inflammation
. N Engl J Med 1998; 338:436–445.
23. Mbopi-Keou FX, Gresenguet G, Mayaud P, Weiss HA, Gopal R, Matta M, et al
. Interactions between herpes simplex virus type 2
and human immunodeficiency virus type 1 infection in African women: opportunities for intervention. J Infect Dis 2000; 182:1090–1096.
24. Schacker T, Ryncarz AJ, Goddard J, Diem K, Shaughnessy M, Corey L, et al
. Frequent recovery of HIV
-1 from genital herpes simplex virus lesions in HIV
-1-infected men. JAMA 1998; 280:61–66.
25. Rebbapragada A, Wachihi C, Pettengell C, Sunderji S, Huibner S, Jaoko W, Ball B. Negative mucosal synergy between Herpes simplex type 2 and HIV
in the female genital tract. AIDS 2007; 21:589–598.
26. Levi G, Feldman J, Holman S, Salarieh A, Strickler HD, Alter S, Minkoff H. Relationship between HIV
viral load and Langerhans cells of the cervical epithelium. J Obstet Gynaecol Res 2005; 31:178–184.
27. Quayle AJ, Kourtis AP, Cu-Uvin S, Politch JA, Yang H, Bowman FP, et al
. T-lymphocyte profile and total and virus-specific immunoglobulin concentrations in the cervix of HIV
-1-infected women. J Acquir Immune Defic Syndr 2007; 44:292–298.
28. Taube JM, Nichols AD, Bornman LS, Bornman DM, Jackson JB. Langerhans cell density and high-grade vulvar intraepithelial neoplasia in women with human immunodeficiency virus infection. J Cutan Pathol 2007; 34:565–570.
29. Behbahani H, Walther-Jallow L, Klareskog E, Baum L, French AL, Patterson BK, et al
. Proinflammatory and type 1 cytokine expression in cervical mucosa during HIV
-1 and human papillomavirus infection. J Acquir Immune Defic Syndr 2007; 45:9–19.
30. Weier S, Muller H, Stutte HJ, Kappus R, Berger S, Shah PM. Lymphocytes, Langerhans cells and CD68-positive monocytes/macrophages in the skin of HIV
-infected patients and normal controls. Verh Dtsch Ges Pathol 1991; 75:114–118.
31. Dreno B, Milpied B, Dutartre H, Litoux P. Epidermal interleukin 1 in normal skin of patients with HIV
infection. Br J Dermatol 1990; 123:487–492.
32. Zhu J, Koelle DM, Cao J, Vazquez J, Huang ML, Hladik F, et al
. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med 2007; 204:595–603.
33. Tobian AA, Charvat B, Ssempijja V, Kigozi G, Serwadda D, Makumbi F, et al
. Factors associated with the prevalence and incidence of herpes simplex virus type 2
infection among men in Rakai, Uganda
. J Infect Dis 2009; 199:945–949.
34. Meier AS, Bukusi EA, Cohen CR, Holmes KK. Independent association of hygiene, socioeconomic status, and circumcision
with reduced risk of HIV
infection among Kenyan men. J Acquir Immune Defic Syndr 2006; 43:117–118.
35. Moore JE. The diagnosis of chancroid and the effect of prophylaxis upon its incidence in the American Expeditionary Forces. J Urol 1920; 4:169–176.
36. O'Farrell N. Soap and water prophylaxis for limiting genital ulcer disease and HIV
-1 infection in men in sub-Saharan Africa. Genitourin Med 1993; 69:297–300.
37. Makumbi F, Gray RH, Wawer M, Nakigozi FG, Serwadda D, Kigozi G, et al. Male postcoital penile cleansing and the risk of HIV-acquisition in rural Rakai district, Uganda.
The 4th International AIDS Society Meeting Abstract # WEAC1LB; Sydney, Australia; 25 July 2007.
38. Donoval BA, Landay AL, Moses S, Agot K, Ndinya-Achola JO, Nyagaya EA, et al
-1 target cells in foreskins of African men with varying histories of sexually transmitted infections. Am J Clin Pathol 2006; 125:386–391.
39. Tokgoz H, Polat F, Tan MO, Erdem O, Bozkirli I. Histopathological evaluation of the preputium in preschool and primary school boys. Int Urol Nephrol 2004; 36:573–576.
40. Feng JY, Peng ZH, Tang XP, Geng SM, Liu YP. Immunohistochemical and ultrastructural features of Langerhans cells in condyloma acuminatum. J Cutan Pathol 2008; 35:15–20.
41. McCoombe SG, Short RV. Potential HIV
-1 target cells in the human penis. AIDS 2006; 20:1491–1495.