The biological impact of circumcision on HIV acquisition

Circumcision is believed to reduce the risk of male infection because it removes the vulnerable tissue inside the foreskin, which contains Langerhans cells (a type of cell particularly vulnerable to HIV infection). The mucosa that covers the inside of the foreskin contains more Langerhans cells than almost any other part of the body except the gut. These are a type of dendritic cell whose job is to ferry foreign particles to the lymph nodes for recognition by the immune system, and which HIV hijacks as part of its infection strategy. In ex-vivo explant models, foreskin mucosa was found to be nine times more vulnerable to HIV infection than cervical tissue.

Uncircumcised men may also be more vulnerable to infection, because the area under the foreskin can retain bacteria acquired during sex, thus increasing the chance that an infection will become established.

In an Australian study,¹ scientists found that the keratin layer, the surface layer of waterproof protein that protects skin against micro-organisms, was thinner on the inside of the foreskin than it was on the outside, or on the glans of the penis, and that there was virtually no keratin on the fraenulum, the strip of flesh connecting the glans and the foreskin. Although there were more Langerhans cells on the outside of the foreskin, they were closer to the surface on the inner surface of the foreskin and on the fraenulum.

In one substudy from the randomised controlled trial (RCT) of circumcision in Rakai, Uganda,² foreskin size in uncircumcised men was found to be related to vulnerability to HIV. The mean foreskin area was significantly higher among those who seroconverted than those who did not (43.3 vs 36.8 cm²). A foreskin area of more than 45.6 cm² had a significantly increased risk of becoming infected with HIV compared to men with the smallest foreskin surface area (adjusted risk ratio, 2.37, 95% CI: 1.05 to 5.31, p = 0.04).

The higher infection rate in men with intact foreskins may be due not only to the greater density of target cells for HIV to infect, but also because the foreskin traps HIV and inflammation-causing bacteria that may be acquired during sex.

One study from Durban in South Africa³ assessed men (56% HIV-positive) attending a sexual-health clinic, for what they called penile wetness (retained moisture between the glans and the foreskin). This may consist of droplets of urine after urination, semen and vaginal fluid after sex, discharge due to urethral STIs, or fluid caused by inflammation of the penile surfaces.

Among the 50% of men assessed as having penile wetness, HIV prevalence was 66%, versus 46% amongst men with none. After adjustment it was determined that penile wetness was associated with a 44% rise in the likelihood of HIV infection.

One of the conclusions of the authors of this study was that teaching men proper penile hygiene might render circumcision unnecessary; but it also suggests that the foreskin may serve as an ‘incubator’ of infection.

Another substudy from the Rakai RCT researchers⁴ analysed penile swabs taken from twelve participants in the study. The twelve members of the follow-up study cohort were randomly chosen from the subset of men who had undergone circumcision and were still HIV-negative one year after the procedure. The Rakai study team used penile swabs taken before circumcision and one year after circumcision to examine how the bacterial population found on the penis had changed.

The most notable difference between the pre-circumcision and post-circumcision samples was a major reduction in anaerobic bacteria. The researchers proposed that the removal of the foreskin may have eliminated a micro-environment that fosters the growth of anaerobic bacteria.

Their hypothesis is bolstered by the observation that the female partners of circumcised men are less likely to develop bacterial vaginosis, a vaginal infection associated with the presence of a higher-than-normal level of anaerobic bacteria.

Anaerobic bacteria may activate Langerhans’ cells in the genital area, which would help explain why circumcision bestows partial protection against HIV. Removal of anaerobic bacteria via circumcision may result in less Langerhans’ activation, leaving the virus with a smaller gateway to infection.

These researchers also suggested that these findings might suggest alternatives to circumcision. They said: “It is important to better understand the biological mechanisms by which male circumcision reduces the risk of HIV infection as this may lead to the development of novel, non-surgical prevention strategies.”

However, they also noted that the reduction in anaerobic bacteria is only one of multiple proposed explanations for why circumcision makes it harder for HIV infection to occur.

Further research is planned to look for specific bacteria associated with greater HIV risk, and to explore how such bacteria might be eliminated.