Circumcision and HIV infection susceptibility
Foreskin contains large concentrations of the types of cells that HIV targets — a finding that helps explain why uncircumcised men may be more prone to HIV infection than circumcised men, according to Chicago-based researchers led by Robert Bailey of the University of Illinois (Am J Pathol 2002, 161:867–873).
Several epidemiological studies suggest that the risk of acquiring HIV is two- to eightfold greater for uncircumcised men than for circumcised men.
To determine why foreskin may be particularly susceptible, the research team examined foreskin from eight boys and six men as well as cervical tissue from six women. Using monoclonal antibody staining and computerized imaging techniques, the team found that adult foreskin contained higher concentrations of CD4 T cells, macrophages and Langerhans’ cells – the cells hijacked by HIV – compared with paediatric foreskin and cervical tissue. In addition, the foreskins of adult men with a history of sexually transmitted disease had the highest proportions of CD4 T cells and Langerhans’ cells, adding to increasing evidence that a previous bout with a sexually transmitted pathogen leaves the body primed for HIV infection.
The researchers also used a technique called explant culture to compare infection rates of outer and inner foreskin, and cervical tissue. Pencil eraser-sized plugs of the tissues were carefully oriented and swabbed with a HIV solution then cultured for 1 day. When analyzed, the samples of the mucosal inner surface of foreskin contained nine times more viral DNA than cervical tissue. Viral DNA was below detection limits in the samples of outer foreskin, which, like skin, contains keratinized cells that form a protective barrier against infectious pathogens.
`‘[The inner surface of] foreskin is definitely a portal of entry for HIV,’’ says lead author Bruce Patterson, a viral pathologist at Children's Memorial Hospital in Chicago. He is currently gearing up to use the explant culture method to screen for microbicidal compounds that can be applied topically to prevent HIV transmission.
Meanwhile, Bailey, who is an epidemiologist, began a 4-year study earlier this year that will compare HIV infection rates in 2800 consenting, HIV-negative young men. Half of them, chosen at random, will be circumcised. So far, approximately 650 men have enrolled in the study, and half have been circumcised. The work is being conducted in Kisumu, Kenya, an area where one-third of the adults are HIV infected. The predominant ethnic group in Kisumu is Luo, who do not traditionally practice male circumcision.
Secretory leukocyte protease inhibitor (SLPI)
SLPI, a protein found in the saliva of newborns reduces their risk of HIV infection from breast milk, according to an international team of researchers reporting in The Journal of Infectious Diseases (2002, 186:1173–1176.)
About 30% of babies born to HIV-positive mothers become infected with the virus, and half of them contract the pathogen through breast milk. While several bodily secretions, including breast milk, semen and tears, contain SLPI, the highest concentrations are in saliva. Earlier studies have shown that, at the concentrations typically found in adult saliva, the protein inhibits replication of HIV in vitro.
To determine if SLPI helps protect newborns, infectious diseases specialist Carey Farquhar of the University of Washington, Seattle, and collaborators periodically measured salivary SLPI levels and HIV infection status of babies born to HIV-positive mothers in Nairobi, Kenya. Of 122 breast-fed infants who were HIV-negative at 1 month of age, seven became HIV-infected by their first birthday. When the researchers compared the salivary SLPI levels of the infants, they found the concentrations at 1 month of age were almost three times higher in the babies who remained uninfected 11 months later. The team calculated that the risk of mother-to-child transmission decreased about 50% for every 100 ng/ml of SPLI in the saliva of 1-month olds.
SLPI thwarts HIV by binding to a host cell transmembrane protein rather than by latching on to HIV itself or directly interfering with viral replication. Pharmaceutical agents that mimic the actions of SLPI might someday play a role in microbicides to prevent heterosexual HIV transmission, says Farquhar. However, preventing breast milk transmission poses particular problems that require ‘‘thinking outside the box,’’ she says. ‘‘We need to think along the lines of what else we can do to prevent babies from getting HIV because in some parts of the world HIV-infected women will continue to breast feed.’'
Charlene Crabb, Paris