Carrageenan and MIV-150 block uptake and transmission of HIV-1 by primary cervico ectoepithelial cells
Poster presentation at Microbicides 2006, Cape Town, 23-26 April
Fernandez-Romero,Jose A.; Turville,Stuart G.; Miller,Todd; Frank,Ines; Robbiani,Melissa; Titchen,Kanani; Maguire,Robin A.; Phillips,David M.
Publication date: 2006
Previous studies have implicated cervico ectoepithelial cells in the sexual transmission of HIV-1. Although there is controversy over their being productively infected, their ability to uptake and transfer HIV could represent an important step in viral transmission. Previous studies have been limited to transformed cell lines, which may not adequately reflect events during sexual transmission of HIV.
Primary human cervico ectoepithelial cells were used to study uptake of AT-2 HIV (inactivated), and HIV and HIV-1. Candidate microbicide compounds were evaluated that may inhibit this process. The entry of inactive HIV-1 was visualized in a confocal microscope after staining with different fluorescent markers. The transmission of infectious HIV-1 and HIV-1 from ectoepithelial cells to PBMCs was also analyzed. For blocking experiments, Carraguard, a carrageenan-based microbicide currently in Phase 3 clinical trials, was evaluated. Laboratory studies indicate that carrageenan is effective in preventing infection by HIV-1 in vitro, SIV in monkeys, and studies in mice showed prevention of HPV induced transformation, and Neisseria gonorrhoeae infection, and HSV-2 infection in vitro as well as in mice. In addition, the non-nucleoside reverse transcriptase inhibitor (NNRTI), MIV-150 was assayed. Previous studies have demonstrated that MIV-150 is highly efficacious in blocking infection by various HIV-1 strains including those resistant to other NNRTIs and protease inhibitors. In addition, studies demonstrated that resistance to MIV-150 is significantly delayed. Previous animal and human studies have shown that MIV-150 is nontoxic, and although the compound is well tolerated, it has poor systemic absorption via oral intake.
The ectoepithelial cells showed the ability to uptake HIV-1. Virus was located in distinct areas suggestive of vesicles. Carrageenan block both HIV and HIV-1 at a concentration of 500 µg/mL. MIV-150 showed the best results inhibiting the transmission of infectious virus from the ectoepithelial cells to PBMCs at a concentration of 10 µM.
Primary cervico ectocervical cells are able to uptake and transfer HIV-1 to target PBMCs, which can be blocked by carrageenan and MIV-150. We speculate that epithelial cells in the lower genital tract could be a reservoir for HIV and that viral uptake in vivo may be blocked by Carraguard and MIV-150.
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