An Australian study has found that male HIV infection may occur through infection of cells on the inner surface of the foreskin and the fraenulum of uncircumcised men. These areas contain HIV-susceptible Langerhans’ cells close to the skin surface of the skin, and are protected with only a thin layer of keratin. The study’s findings were published in the 13th July edition of AIDS.
Up to 90% of the 18.7 million HIV-positive men in the world were infected through heterosexual intercourse. However, recent observational and randomised controlled studies have found that removal of the foreskin by circumcision can reduce the risk of female-to-male transmission by around 65%.
To establish which HIV-susceptible cells are the initial sites of infection, two investigators from Melbourne examined thin slices of the penises and foreskins of 38 HIV-negative men under the microscope. They looked at nine penises obtained from men who had died and whose bodies had been preserved less than 24 hours previously, as well as fresh foreskins removed from 21 living men undergoing circumcision and eight men who had died.
Firstly, the investigators looked at the thickness of the layer of keratin on different parts of the penis, scoring thickness on a scale of zero to five. They found that the inner surface of the foreskin, which is not exposed when the penis is flaccid, had a thinner keratin layer than both the outer surface (1.8 vs. 3.3 units) and the ‘glans’ or head of the penis (3.3 units; p
Similarly, the fraenulum, the thin strip of flesh on the underside of the penis that connects the shaft to the head, had almost no keratin layer. Keratin is a protein found in skin cells that forms a barrier to prevent HIV entering the body through the skin.
They also looked at the distribution of cells that can be infected with HIV after using an antibody-based staining method. Although the Langerhans’ cells were found at greatest density in the outer foreskin, these cells were closest to the surface of the skin in the inner surface of the foreskin and in the fraenulum. Langerhans’ cells are responsible for picking up disease-causing organisms and taking them to the lymph nodes to inform the immune system, so they are thought to be a major route to HIV infection.
“Superficial Langerhans’ cells on the inner aspect of the foreskin and fraenulum are poorly protected by keratin and thus could play an important role in primary male infection,” the investigators write. “These findings provide a possible anatomical explanation for the epidemiologically observed protective effect of male circumcision.”
Other HIV-susceptible cells including dendritic cells, CD4 T-cells and macrophages were only found in deeper layers of the skin, so are unlikely to be the route of HIV infection unless the skin is broken or inflamed.
The researchers explain that the inner surface of the foreskin is exposed to the outside and stretched when the penis is erect, thus putting it into direct contact with HIV-infected vaginal secretions during unprotected sex. However, they also point out that the cavity formed by the foreskin around the head of the penis could act as a store for HIV after sexual intercourse, extending the time for which the inner foreskin is exposed to the virus.
The investigators also found that the urethra, the tube that carries urine and semen, contained no keratin, while the opening of the urethra had very little. However, these areas of the penis contained very few HIV-susceptible cells, so are unlikely to be routes for HIV infection.
Conversely, the outer surface of the foreskin and the glans contain HIV-susceptible cells, but are protected by a thick layer of keratin.
McCoombe SG et al. Potential HIV-1 target cells in the human penis. AIDS 20: 1491-1495, 2006.