| Heterosexual contact is the predominant mode of HIV transmission worldwide. A small percentage of women at the highest risk of infection (such as commercial sex workers and the partners of HIV+ men) remain uninfected for years, possibly protected from infection by an unknown mechanism. DC-SIGN is an HIV receptor expressed on the surface of dendritic cells, including those in the lamina propria of vaginal and rectal inucosae, and is thought to play a role in the transmission of HIV across mucosal surfaces. I hypothesized that the apparent protection observed in HIV-exposed, persistently seronegative women might be due to inhibition of HIV-DC-SIGN interactions in the genital tract. Cervico-vaginal lavages (CVLs) were collected from 95 women at both high and low risk of heterosexual exposure to HIV, and 12.6% were able to inhibit binding of HIV to DC-SIGN in a dose dependent manner, regardless of risk of exposure. DC-SIGN binding of both R5 and X4 lab-adapted strains of HIV-1 were inhibited, as well as the trans-infection of most, but not all, R5 primary isolates. Further evidence suggests that not all primary isolates are equally capable of DC-mediated trans -infection. The proposed mechanism of the inhibitor is blocking gp120 by binding to DC-SIGN. Preliminary characterization of the substance indicates that it is at least 50 kiloDaltons in size, heat stable, trypsin resistant, and pronase sensitive. It is antibody independent and does not contain terminal mannose or LewisX antigens. Activity of CVLs is weakly associated with a history of at least one HIV+ sexual partner. There was also a negative association with white blood cells. There was no association with vaginitis or other risk factors or clinical observations, but anecdotal evidence suggests a negative role for bacterial vaginosis. Further study of this putative inhibitor and additional primary isolates could help elucidate the role of dendritic cells in HIV transmission, as well as provide the basis for a method of prevention. |
