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A new study conducted by Chicago researchers shows that internal mucosal layers of foreskin are more susceptible to HIV infection than cervical tissue or the external layers of foreskin, which explains why uncircumcised men seem to be at much higher risk for HIV acquisition than men who are circumcised.

Previously, numerous studies reported that uncircumcised men have higher rates of HIV infection and are at a twofold to eightfold increased risk of becoming infected with HIV compared to circumcised men. However, why circumcision plays a protective role against acquisition of HIV has been unknown.

A study published in the September issue of the American Journal of Pathology by researchers at Rush-Presbyterian-St. Luke’s Medical Center, Children’s Memorial Hospital and the University of Illinois at Chicago School of Public Health points to the biological mechanisms underlying this protective effect.

The researchers examined foreskin tissue obtained from eight children and six adults who were undergoing circumcision for other reasons. Those tissues were compared with cervical tissue, which served as controls. The analysis showed that foreskin mucosa (cells underneath the surface) contain high concentrations of the cells targeted by HIV. The foreskin tissue contained higher densities of CD4+ T cells, macropahges and Langerhans’ Cells (LC) in adults than in children or in cervical tissue. The highest proportion of these HIV target cells were found in men with a history of infection, which is consistent with studies finding that men with sexually transmitted infections are more susceptible to HIV.

According to Alan Landay, PhD, department of Immunology/Microbiology and at Rush-Presbyterian-St. Luke’s Medical Center, the higher the concentration of HIV target cells, the more susceptible the tissue is to HIV. This proved to be the case. When the authors introduced HIV to the tissue in culture, the cells in the foreskin tissues were infiltrated with HIV rapidly and at much greater intensity than the cervical tissue.

According to the first author, Bruce Patterson, M.D, viral pathologist in the division of Infectious Diseases at Children’s Memorial Hospital, there are logical, but as yet unproven theories explaining how HIV infection occurs in the circumcised penis. "Infection may occur through the urethral mucosa or through disruptions of the penile shaft epithelia caused by genital ulcer disease or trauma," he said. In uncircumcised men, Patterson said that the thin keratin layer they found on the inner compared to the outer mucosal surface predisposed the foreskin to infection.

The authors mention that a limitation of the study is that they were unable to obtain tissue from circumcised penises for comparison.

However, the study’s senior author, Robert Bailey, PhD, MPH, from the Division of Epidemiology, School of Public Health at the University of Illinois at Chicago, is conducting a study in east Africa that will address this issue. Bailey and his collaborators have begun a randomized controlled trial to compare HIV acquisition in 1,400 African males age 18-24 who will be circumcised with 1,400 in the same city who are not circumcised. Bailey’s team will take two years to recruit all the young men and will follow each group for two years, providing them with HIV prevention counseling and free medical treatment. After four years of study, they will be able to determine if circumcision reduced the men’s chances of becoming HIV infected.

Landay said that the implications of this foreskin tissue evaluation and the positive association between uncircumcisized individuals and HIV acquisition indicate that strong consideration should be given to integrating male circumcision information and services with other HIV preventive methods.

To reach Bruce Patterson, call Julie Pesch at Children’s Memorial Hospital, 773/880-3055. To reach Robert Bailey, call Sherri McGinnis at the University of Illinois at Chicago 312/996-8277, or call Bailey directly at 312-355-0440..