The male foreskin—an unassuming flap of skin eagerly discarded in some cultures—has taken center stage in recent debates over HIV prevention. Although researchers now agree that its removal is a proved method to reduce HIV spread in heterosexual men, the picture for homosexual men remains a bit foggy.

In the late 1980s observations of heterosexual men in Africa indicated that those who had been circumcised might be at less risk of contracting HIV than men who left their foreskins intact. To definitely test the hypothesis, researchers initiated clinical trials in at-risk populations with low rates of circumcision.

Two studies focused on young urban men (ages 18 to 24) in Kenya and South Africa, whereas a third concentrated on a larger cross-section of rural men (ages 15 to 49) in Uganda. Over 11,000 men volunteered for the trials with one group receiving circumcision on enrollment and a control group delaying surgery until the end of the study.

By tracking newly acquired infections in both groups, investigators discovered that circumcision cut HIV transmission rates by 55 to 65 percent. In fact, all three trials were stopped early due to the overwhelming evidence of circumcision's protective effect.

"It was striking that the trials were in very different settings, but yielded consistent results," says Ronald Gray, study leader for the Uganda trial and epidemiologist at Johns Hopkins Bloomberg School of Public Health in Baltimore. "This was the largest protective effect ever seen next to condom use," adds Sten Vermund, director of the Institute for Global Health at Vanderbilt University School of Medicine in Nashville, Tenn. But the question remained: Why?

Microscopic examination of the foreskin yielded important clues for unraveling the benefits of circumcision. Normally, the skin provides a thick protective barrier stemming from keratin—a tough structural protein also found in hair and fingernails. But on the inner surface of the foreskin, the keratin layer is much thinner, resembling the inner lining of the mouth or eyelid more than the palm of the hand.

In uncircumcised men Langerhans cells—immune cells that are primary targets for HIV transmission—"are more richly concentrated near the surface of the foreskin," says Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Md. Without the keratin barrier, HIV can easily access these cells in the foreskin. Following infection, Langerhans cells not only serve as reservoirs for replicating virus, but also transport the virus to nearby lymph nodes where HIV spreads to other immune cells.

In fact, the foreskin's anatomical function actually amplifies the risks. In uncircumcised men the foreskin covers and protects the tip of the penis, paradoxically making the skin there more delicate and prone to microscopic abrasions. These tiny injuries promote inflammation, Fauci says, allowing the virus to come into closer contact with target immune cells. The moist environment that forms under the foreskin also enhances the growth of microbes on the penis's tip, Fauci adds, further stimulating immune responses near the skin's surface.

At the very least, Vermund notes, the foreskin increases contact time with the virus following unprotected sexual intercourse when infectious fluid becomes trapped.

Although the benefits and efficacy of circumcision are now well documented for heterosexual men, the role of foreskin removal in homosexual men remains an open question. To date, no clinical trial has been conducted to assess if circumcision may be protective for this population. But researchers recently combined the results of 15 observational studies in a meta-analysis conducted in the U.S., Europe and several developing nations involving over 53,000 homosexual men to determine if any evidence for protection exists.

Mathematical analyses indicated that HIV risk was reduced by 14 percent in circumcised homosexual men across the studies, but "the results were not statistically significant, pointing to the possibility that circumcision may not have a substantial effect on HIV infection in men who have sex with men," says Gregorio Millett, study author and a behavioral scientist at the U.S. Centers for Disease Control and Prevention in Atlanta.

The difficulty in evaluating circumcision for homosexual populations, notes Gray, is that most studies do not carefully evaluate sexual practices. Although foreskin removal protects men engaged in anal intercourse (in the same manner as it benefits heterosexual men), "nothing about circumcision protects receptive men as the rectal area is exposed to HIV," Vermund says. The issue will likely remain unresolved until more data can be gathered from studies specifically designed to address the effects of circumcision on the various subgroups of homosexual men.

Current recommendations from the World Health Organization (WHO) in Geneva, Switzerland, call for large-scale circumcision campaigns in countries with high infection rates. For sub-Saharan Africa (where heterosexual sex is primarily responsible for the HIV epidemic), circumcision has the potential to dramatically reduce the toll of the virus, which WHO estimates of up to 5.7 million new infections and three million deaths averted over the next 20 years.

Fauci does not foresee a broad mandate for circumcising infants in the U.S., however, where the practice is already common. "Although circumcision could be beneficial," he says, "HIV is not a disease of the general population here."

Despite the protective effect of circumcision, condoms remain a key component of HIV prevention, because there is "no surgical way to remove all of the inner foreskin," cautions Roger Short, a reproductive biologist at the University of Melbourne in Australia.

In the future, alternatives to circumcision may become available for those men with social or religious objections to the practice. Estrogen creams have recently been proposed as their application sparks a rapid deposition of keratin in the foreskin. If the foreskin can be sufficiently reinforced with keratin to provide a barrier for the Langerhans cells, Short says, a weekly topical application of estrogen could augment or even replace circumcision. For now, however, researchers remain skeptical, as estrogen may also increase the number of HIV receptors on the surface of target cells.

The bottom line: circumcision protects heterosexual men from HIV acquisition via sexual intercourse with the greatest benefits accruing in developing nations that are hardest hit by the epidemic.