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British Medical Journal, June 10, 2000, by Robert Szabo, Roger V Short

Bs'd

How does male circumcision protect against HIV infection?

British Medical Journal, June 10, 2000, by Robert Szabo, Roger V Short

Summary points

The majority of men who are HIV positive have been infected through
the penis

There is conclusive epidemiological evidence to show that
uncircumcised men are at a much greater risk of becoming infected with
HIV than circumcised men

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

The development of HIV receptor blockers, which could be applied to
the penis or vagina before intercourse, might provide a new form of
HIV prevention

In his otherwise excellent review of the AIDS epidemic in the 21st
century, Fauci presented no new strategies for preventing the spread
of the disease.[1] He made no mention of male circumcision, yet there
is now compelling epidemiological evidence from over 40 studies which
shows that male circumcision provides significant protection against
HIV infection; circumcised males are two to eight times less likely to
become infected with HIV.[2] Furthermore, circumcision also protects
against other sexually transmitted infections, such as syphilis and
gonorrhoea,[3 4] and since people who have a sexually transmitted
infection are two to five times more likely to become infected with
HIV,[5] circumcision may be even more protective. The most dramatic
evidence of the protective effect of circumcision comes from a new
study of couples in Uganda who had discordant HIV status; in this
study the woman was HIV positive and her male partner was not.[6] No
new infections occurred among any of the 50 circumcised men over 30
months, whereas 40 of 137 uncircumcised men became infected during
this time. Both groups had been given free access to HIV testing,
intensive instruction about preventing infection, and free condoms
(which were continuously available), but 89% of the men never used
condoms, and condom use did not seem to influence the rate of
transmission of HIV. These findings should focus the spotlight of
scientific attention onto the foreskin. Why does its removal reduce a
man's susceptibility to HIV 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.

In vitro studies have shown that the CD4 receptor is generally
necessary, although insufficient on its own, to permit HIV-1 to enter
host cells.[11] The entry of HIV-1 into cells requires an additional
chemokine receptor, usually CCR5, although CXCR4 is used by cells that
become infected during the later stages of the disease.[12] After
primary infection occurs, the virus mutates, which allows it to
utilise other chemokine receptors, such as CXCR4, and thus spread to a
variety of cell types. However, more than 99% of HIV-1 isolates from
acutely infected patients are homologous, indicating that one specific
variant is likely to be responsible for most cases of primary HIV
infection.[13] HIV variants that are transmitted to other individuals
almost invariably use CCR5 as a coreceptor and are therefore named R5
viruses, to reflect their specific requirement for a coreceptor.[14]

How HIV enters the penis

About 70% of men infected with HIV have acquired the virus through
vaginal sex, and a smaller number have acquired it from insertive anal
intercourse.[7] Thus, on a global scale most men who are HIV positive
have acquired the virus via the penis. This raises questions of how
HIV enters the penis and why men who are uncircumcised are potentially
more susceptible to becoming infected with HIV.

The uncircumcised penis consists of the penile shaft, glans, urethral
meatus, inner and outer surface of the foreskin, and the frenulum, the
thin band connecting the inner foreskin to the ventral aspect of the
glans. 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 keratinised[15] 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.

There is controversy about whether the epithelium of the glans in
uncircumcised men is keratinised; some authors claim that it is
not,[15] but we have examined the glans of seven circumcised and six
uncircumcised men, and found the epithelia to be equally keratinised.
In circumcised males only the distal penile urethra is lined with a
mucosal epithelium. However, this is unlikely to be a common site of
infection because it contains comparatively few Langerhans' cells.[10]

Ulcerative or inflammatory lesions of the penile urethra, foreskin,
frenulum, or glans that are caused by other sexually transmitted
infections may provide additional potential routes for HIV
transmission. In uncircumcised males, the highly vascular frenulum is
particularly susceptible to trauma during intercourse, and lesions
produced by other sexually transmitted infections commonly occur
there. Thus, male circumcision further reduces the risk of infection
by reducing the synergy that normally exists between HIV and other
sexually transmitted infections.[5]

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.

It may also be time to re-think the definition of "safe sex." Since
the penis is the probable site of viral entry, neither infected semen
nor vaginal secretions should be allowed to come in contact with the
penis, particularly in uncircumcised males. Thus, mutual male
masturbation during which a penis is exposed to the potentially
infected semen of another male should be regarded as risky sexual
behaviour.

New preventive strategies are needed that could be used by men or
women before the onset of intercourse. The disadvantage of topical
virucides, such as nonoxinol 9, is that they may cause local
irritation and thus increase susceptibility to HIV infection. The
development of topically active agents that could block HIV binding
sites, such as CCR5, and which could be applied to the penis or vagina
to create a "chemical condom," might be more effective and acceptable
than any mechanical barrier or surgical intervention.

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.

Funding: None.

Competing interests: None declared.

[1] Fauci AS. The AIDS epidemic: considerations for the 21st century.
N Engl J Med 1999;341:1046-50.

[2] Halperin DT, Bailey RC. Male circumcision and HIV infection: 10
years and counting. Lancet 1999;354:1813-5.

[3] Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually
transmitted diseases. Am J Public Health 1994;84:197-201.

[4] Moses S, Bailey RC, Ronald AR. Male circumcision: assessment of
health benefits and risks. Sex Transm Infect 1998;74:368-73.

[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.

[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;342:921-9.

[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;183:215-25.

[9] Miller CJ. Localization of simian immunodeficiency virus-infected
cells in the genital tract of male and female rhesus macaques. J
Reprod Immunol 1998;41:331-9.

[10] Hussain LA, Lehner T Comparative investigation of Langerhans
cells and potential receptors for HIV in oral, genitourinary and
rectal epithelia. Immunology 1995;85:475-84.

[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;3:1369-75.

[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;381:667-73.

[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;261:1179-81.

[14] Kahn JO, Walker BD. Acute human immunodeficiency virus type 1
infection. N Engl J Med 1998;339:33-9.

[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.

(Accepted 11 May 2000)

Faculty of Medicine, Monash University, Wellington Road, Melbourne
3168, Australia

Robert Szabo medical resident

Department of Obstetrics and Gynaecology, University of Melbourne,
Royal Women's Hospital, 132 Grattan Street, Melbourne 3053, Australia

Roger V Short professor

Correspondence to: R V Short

BMJ 2000;320:1592-4

COPYRIGHT 2000 British Medical Association in association with The
Gale Group and LookSmart.
COPYRIGHT 2000 Gale Group

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