Background: The relative importance of cell-associated vs cell-free HIV-1 in sexual transmission of the virus is unknown. Previous studies in our laboratory using in vitro and in vivo systems modeling movement of virus across an epithelial barrier have demonstrated more efficient transmission of cell-associated virus. We hypothesize that antibodies directed at ligands involved in migration of cells across an epithelial barrier will interrupt movement of virus across the type of epithelial barriers that line the vaginal mucosa.

Methods: The transmission of HIV-1 by infected PBMC or cell-free virus across human cervical epithelial cells was examined using a transwell culture system and a recently described model of vaginal transmission in mice with severe combined immunodeficiency transplanted with human peripheral blood mononuclear cells (SCID-hu-PBL mice). Monoclonal antibody (Mab) specific for ICAM-1 was added to these systems prior to viral challenge. ANOVA was used to compare the differences between groups, and the Fisher exact test was used to compare the difference between experimental groups. Significance was defined as p < 0.05.

Results: In the transwell system, anti-ICAM-1 Mab reduced the transmission of monocyte-associated HIV-1 by 99% (p < 0.01); Mab to e-cadherin, aeb7, and LFA-1 did not block transmission. Anti-ICAM-1 Mab also blocked trans-epithelial transmission by HIV-transfected 293T cells expressing neither ICAM-1 nor its ligands (p < 0.02), suggesting that anti-ICAM-1 is reacting with ICAM-1 on the epithelial cells and is acting by mechanisms not simply involving docking between ICAM-1 and its ligands on transmitting cells. In vivo, vaginal exposure to 10 ml of anti-murine ICAM-1 Mab (20 mg/ml) 5 minutes prior to challenge resulted in infection of 1/9 mice, while 5/7 isotype control and 5/6 PBS control mice were infected (p < 0.02).

Conclusions: Anti-ICAM-1 Mab efficiently blocks transmission of cell-associated virus across epithelial surfaces in vitro and in vivo. Our findings indicate that anti-ICAM-1 was blocking by engagement of ICAM-1 on epithelial cells and was not acting by simply interfering with ICAM-1’s function as a docking molecule. Our lab is currently investigating the effects of ICAM-1 engagement on signal transduction pathways that might influence epithelial barrier permeability.