circumcision - HIV - Langerhans cells

"If in doubt, circumcise!"

Langerhans cells in the foreskin and HIV transmission:
contrary findings, one conclusion

Langerhans cells, along with other classes of dendritic cells, are universally found in all skin,. There is minimal variation between parts of the body in their content of Langerhans cells. They are found in all genital tissue including the glans, foreskin, shaft, scrotum, clitoris, clitoral hood, labia, and vagina.
While Szabo and Short argue that the foreskin has MORE Langerhans cells than ordinary skin, Gerald Weiss argues that it has FEWER Langerhans cells.
Predictibly, both conclude from this contradictory data that circumcision will protect men against HIV and AIDS.
Szabo and Short's article is analysed in full on another page.
BMJ 2000;320:1592-1594 ( 10 June )

Education and debate

How does male circumcision protect against HIV infection?

Robert Szabo, medical resident a Roger V Short, professor b

a Faculty of Medicine, Monash University, Wellington Road, Melbourne 3168, Australia, b Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women's Hospital, 132 Grattan Street, Melbourne 3053, Australia

Correspondence to: R V Short


Summary points


The inner surface of the foreskin contains Langerhans' cells with HIV receptors; these cells are likely to be the primary point of viral entry into the penis of an uncircumcised man

Male circumcision should be seriously considered as an additional means of preventing HIV in all countries with a high prevalence of infection

 >   Methods

To compile the information for this review a Medline search was done using the terms circumcision, HIV, Langerhans' cells, penis, foreskin, and prepuce, and extensive email correspondence with other researchers was also undertaken. Histological observations were carried out on samples of penile tissue obtained from 13 perfusion fixed cadavers of men aged 60-96 years, seven of whom had been circumcised.

 >   The pathogenesis of sexually acquired HIV infection

Between 75% and 85% of cases of HIV infection worldwide have probably occurred during sexual activity.7 Most cases of primary HIV infection are thought to involve HIV binding initially to the CD4 and CCR5 receptors found on antigen presenting cells - which include macrophages, Langerhans' cells, and dendritic cells - in the genital and rectal mucosa.

...The most widely accepted model for the sexual transmission of HIV is based on infection of the genital tract of rhesus macaques with simian immunodeficiency virus. 8 9 After female macaques are inoculated intravaginally with simian immunodeficiency virus, the virus targets the Langerhans' cells located in the vaginal mucosa. Once infected, these cells fuse with adjacent CD4 lymphocytes and migrate to deeper tissues. Within two days of infection, the virus can be detected in the internal iliac lymph nodes and shortly thereafter in systemic lymph nodes. This ultimately leads to a fatal infection.

Similarly, infection in male macaques occurs when simian immunodeficiency virus is inoculated into the penile urethra or onto the foreskin; the same sequence of cellular events involving the infection of Langerhans' cells is then likely to occur.9 Infected Langerhans' cells have also been detected in the penile mucosa of male rhesus macaques that have chronic simian immunodeficiency virus infection.9 In humans, histological studies have identified antigen presenting cells in the mucosa of the inner foreskin and urethra.10 Therefore it seems likely that antigen presenting cells at these mucosal sites are the primary target for HIV in men.

...[Detail of infection mechanism omitted]
 >   How HIV enters the penis


... A keratinised, stratified squamous epithelium covers the penile shaft and outer surface of the foreskin. This provides a protective barrier against HIV infection. In contrast, the inner mucosal surface of the foreskin is not keratinised15 and is rich in Langerhans' cells,10 making it particularly susceptible to the virus. This is particularly important because during heterosexual intercourse the foreskin is pulled back down the shaft of the penis, and the whole inner surface of the foreskin is exposed to vaginal secretions, providing a large area where HIV transmission could take place.



 >   Conclusions

Of the estimated 50 million people infected with HIV worldwide, about half are men, most of whom have become infected through their penises. The inner surface of the foreskin, which is rich in HIV receptors, and the frenulum, a common site for trauma and other sexually transmitted infections, must be regarded as the most probable sites for viral entry in primary HIV infection in men. Although condoms must remain the first choice for preventing the sexual transmission of HIV, they are often not used consistently or correctly, they may break during use, and there may be strong cultural and aesthetic objections to using them. Cultural and religious attitudes towards male circumcision are even more deeply held, but in the light of the evidence presented here circumcising males seems highly desirable, especially in countries with a high prevalence of HIV infection. Although neonatal circumcision is easy to perform, and has a low incidence of complications,16 it would be 15-20 years before a programme of circumcision had any effect on HIV transmission rates. Circumcision at puberty, as practised by many Muslim communities, would be the most immediately effective intervention for reducing HIV transmission since it would be done before young men are likely to become sexually active.

[This tendentious argument is refuted more fully on another page.]

It may also be time to re-think the definition of "safe sex." ...


 >   Acknowledgments

We thank Professor John Mills for helpful comments on an early draft of the manuscript and Professor Daine Alcorn and the staff of the Department of Anatomy, University of Melbourne, for supplying and processing the specimens from human cadavers.

Contributors: RS reviewed all the relevant literature, carried out the histological examination of the specimens, and wrote the first draft of the manuscript. RVS initiated the study and participated in redrafting of the paper. Both authors will act as guarantors.

 >   Footnotes

Funding: None.

Competing interests: None declared.

 >   References

1. Fauci AS. The AIDS epidemic: considerations for the 21st century. N Engl J Med 1999; 341: 1046-1050[Medline].
2. Halperin DT, Bailey RC. Male circumcision and HIV infection: 10 years and counting. Lancet 1999; 354: 1813-1815
[An unreferreed opinion-piece.] [Medline].
3. Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually transmitted diseases. Am J Public Health 1994; 84: 197-201[Medline].
4. Moses S, Bailey RC, Ronald AR. Male circumcision: assessment of health benefits and risks. Sex Transm Infect 1998; 74: 368-373[Medline].
5. 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[Medline].
6. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000; 342: 921-929 [Medline].
7. Joint United Nations Programme on HIV/AIDS. The HIV/AIDS situation in mid 1996: global and regional highlights. Geneva: United Nations, 1996. (UNAIDS fact sheet 1 July 1996.)
8. Spira AI, Marx PA, Patterson BK, Mahoney J, Koup RA, Wolinsky SM, et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996; 183: 215-225[Abstract].
9. Miller CJ. Localization of simian immunodeficiency virus-infected cells in the genital tract of male and female rhesus macaques. J Reprod Immunol 1998; 41: 331-339[Medline].
10. Hussain LA, Lehner T. Comparative investigation of Langerhans cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology 1995; 85: 475-484[Medline].
11. Zaitseva M, Blauvelt A, Lee S, Lapham CK, Klaus-Kovtun V, Mostowski H, et al. Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nature Med 1997; 3: 1369-1375[Medline].
12. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381: 667-673[Medline].
13. Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, et al. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 1993; 261: 1179-1181[Medline].
14. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998; 339: 33-39[Medline].
15. Barreto J, Caballero C, Cubilla A. Penis. In: Sternberg SS, ed. Histology for pathologists. 2nd ed. Philadelphia: Lippincott-Raven, 1997.
16. Morris B. In favour of circumcision. Sydney: University of New South Wales Press, 1999. [Damned by the critics. The level of Morris's scholarship may be seen on this site.]

(Accepted 11 May 2000)

Israel Journal of Medical Sciences, Vol 29 No 1, January 1993

The Distribution and Density of Langerhans Cells in the Human Prepuce: Site of a Diminished Immune Response?

by Gerald N. Weiss, Melinda Sanders and Kent. C. Westbrook

The possible role of the human prepuce in sexually transmitted disease and neoplasia led us to evaluate one component of the body's epithelial immune system, the intraepithelial Langerhans cell. The study was prompted by a report stating that Langerhans cells harbor the human immunodeficiency virus, type 1 (HIV-1) [1], and a subsequent African controlled case study indicating that uncircumcised men were more likely to be seropositive for HIV-1 than the circumcised [2]. The Langerhans cell is an epithelial component of the immune system...

The epidermal Langerhans cells (ELC) play a role in the recognition and processing of antigens in order to present them to either lymphocytes and/or macrophages. They may represent the first contact of viral antigens with the cellular immune system of the skin and squamous mucosa as found in the human prepuce.

It has been shown experimentally in the mouse that skin deficient in ELC (induced by ultraviolet exposure) is unable to mount hypersensitivity reactions to 2,4-dinitro-1-fluorobenzene [3]. Those authors speculate that the ELC form a "network" that renders cutaneously applied antigens immunogenic. The absence of such a network renders the host unresponsive. We undertook a study of the count of ELC in the neonatal prepuce that could act as a baseline for comparing the cell population in the circumcised and uncircumcised male.


Unfixed foreskins were obtained from all neonates undergoing circumcision at the University Hospital of Arkansas between 7 November 1988 and 6 January 1989. [Details of staining and processing of samples omitted.]


The prepuce can be divided morphologically into an outer and inner surface. The inner surface is characterized by the absence of keratinization and skin appendages, thickening of the epithelium, special sebaceous glands (Tyson's) at its junction with the corona, a relative decrease in melanocytes, and is recognized as a squamous mucosal surface. The transition between outer and inner surfaces was sharply demarcated in 22 cases. The sections stained with OKT6 also showed an abrupt transition. The outer surface of the prepuce exhibited a relative abundance of ELC. The inner surface showed virtually no such cells. The external surface exhibited a mean ELC count of 174 +/- 15 cells/sq. mm and the internal surface exhibited a mean cell count of 8.0 +/- 2.4 cells/sq. mm (P <0.001). Fig. 1 graphically illustrates the data from these findings.


Our study shows a scarcity of ELC on the inner aspect of the neonatal prepuce. The outer surface exhibited cell counts comparable to those seen in a study of human skin [4]. A search of the literature failed to reveal a comparative study of ELC at the outer and inner surfaces of the human prepuce. This lack of ELC at the inner surface may result in a squamous mucosa with reduced immunological responsiveness to cutaneous antigens.

Considering the role of prophylaxis in disease, this investigation favors the re-emphasis of the medical value of neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision [5], and Wiswell [6], a prominent neonatologist formerly opposed to circumcision, have recently revised their thinking on this issue. [The AAP does not recommend neonatal circumcision.] Wiswell now speaks of the many potential advantages to the neonate and reports that circumcision prevents urinary tract infections, penile cancer, sexually transmitted diseases and perhaps AIDS. [Wiswell spent years desperately looking for a reason to support circumcision.] He also notes that "To date, no studies have supported the assertion that good hygiene averts the potential complications of the uncircumcised state." Careful removal of the prepuce by trained practitioners can be done with no mortality and a complication rate not exceeding 0.1% [7]. ["Can" covers a multitude of sins.] A mundane consideration is that it is economically more feasible to circumcise early in life. ["Economically more feasible?" Or more profitable, because the babies never refuse?]

The discovery of the scarcity of ELC at the neonatal inner prepuce may be indicative of this site's vulnerability to infection and neoplasia [8]. Although the role of circumcision remains controversial, our study when coupled with recent scientific and epidemiological data suggests a pressing need for neonatal posthetomy [circumcision] as a prophylactic surgical procedure.


1. Kolanta G. Where is the AIDS virus harbored? Science 1986;232:1197.

2. Sirnonsen JN, Cameron DW, Galinya MN, et al. Human immunodeficiency virus infection among men with sexually transmitted diseases. N Engl J Med 1988;319:274-278.

3. Streilein JW, Toews GT, Gilliam JN, et al. Tolerance or hypersensitivity to 2,4-dintro-l fluorobenzene: the role of Langerhans cell density within epidermis. J Invest Dermatol 1980;74:319-321.

4. Berman B, Chen VL, France DS, et al. Anatomic mapping of epidermal Langerhans cell densities in adults. Br J Dermatol 1983;109:553-558.

5. American Academy of Pediatrics Task Force on Circumcision. Report of the Task Force on Circumcision. Pediatrics 1989;84:388-391.

6. Wiswell T. Routine neonatal circumcision: a reappraisal. Am Fam Physician 1990,41:859-863.

7. Shulman J, Ben-Hur N, Newman Z. Surgical complications of circumcision. Am J Dis Child 1978;107:149-154.

8. Bonilla-Musoles F, Castells A, Simon C, et al. Importance of Langerhans cells in the immune origin of carcinoma of the uterine cervix. Eur J Gynaecol Oncol 1987;VIII(1): 44-60.


It is an epidemiological fact that cancer of the penis and infection of the foreskin area are more common in the uncircumcised than the circumcised. [The first is not a fact. The second? Well, d'uh.] For over a century, the medical literature has been replete with these findings related to neoplasia, STD and circumcision. Recognition of preputial cellular deficiency of Langerhans cells at the mucosal surface allows for a better understanding of cellular immune reactions at this site. This knowledge of penile vulnerability in the neonate reinforces the need for early posthetomy [circumcision] as a prophylactic measure. ...

Gerald N. Weiss, M.D.
Diplomate American Board of Surgery
Fellow American College of Surgeons
Fellow International College of Surgeons



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