A scanning electron micrograph of a budding HIV-1 virus
CDC / C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus

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.