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]