Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of human immunodeficiency virus-1

Abstract

We have previously suggested that sulfated polysaccharides could be used in a vaginal formulation to inhibit infection by human immunodeficiency virus (HIV-1). This supposition was based on studies in which we developed and employed an in vitro model to simulate the mechanism of HIV-1 transmission during coitus. We found that adhesion of mononuclear cells to epithelia was the initial step in infection and speculated that blocking adhesion would prevent HIV-1 transmission. We observed that certain sulfated polysaccharides prevented adhesion of lymphoma cell lines to epithelial cell lines, which were derived from the genital tract, in concentrations of a few milligrams per milliliter; and we theorized that sulfated polysaccharides could thus be used as active ingredients in a topical "microbicide." In the present in vitro study, evidence is presented that a number of sulfated polysaccharides, including carrageenan, dextran sulfate, heparin, fucoidan, and pentosan polysulfate, are capable of blocking infection by mechanisms other than adhesion at concentrations of a thousand times lower than the dosages that are needed to block cell adhesion. One of these compounds, iota carrageenan, is capable not only of blocking infection of epithelia at concentrations of 1-2 micrograms, but of blocking adhesion to a far greater extent than the other sulfated polysaccharides tested. For this reason, as well as for considerations of safety, stability, and gelling properties, we suggest that iota carrageenan may be the best choice of the sulfated polysaccharides tested for use as a vaginal microbicide. The same in vitro model was employed to decipher the cell surface molecules involved in lymphocyte-to-epithelial adhesion. To accomplish this, we screened for the presence of cell adhesion molecules (CAMs), carbohydrates, proteoglycans, and carbohydrate-binding sites. HIV-1-infected lymphocytic cells expressed a CAM profile typical of activated, infected cells (e.g., HLA-DR+, CD4-, LFA-1+, ICAM-1+, LFA-3+, CD2+) whereas epithelia expressed few CAMs (LFA-3, ICAM-1, VLA-5, CD44, CD26, sLEX). Both cell types expressed heparan sulfate and chondroitin sulfate proteoglycans. A variety of sugars (mannose, fucose, galactose, Nac-galactosamine, Nac-glucosamine) were also present, but these cells expressed few carbohydrate-binding sites; lymphocytes bound beta-galactose. We were unable to block the adhesion with anti-CAM antibodies or with exogenous sugars. When enzymes were used against sulfated cell surface molecules, chondroitinase was found to block the adhesion. Our evidence suggests that this CAM-independent adhesion may be a lectin-glycosaminoglycan interaction.

Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

“…Thorough characterization of vaginal and cervical epithelial cells, as well as HIV-1-infected mononuclear cells, has identified several relevant adhesion molecules, including ICAM-1 (46,47), that may facilitate the binding of infected cells to the epithelium (47,48). ICAM-1 is highly expressed by monocytes (49) and epithelial cells (46) and, to a lesser extent, by activated lymphocytes including HIV-1 infected CD4 ϩ T cells (47), and it plays a significant role in transendothelial migration of T lymphocytes and monocytes (20 -23).…”

“…ICAM-1 is highly expressed by monocytes (49) and epithelial cells (46) and, to a lesser extent, by activated lymphocytes including HIV-1 infected CD4 ϩ T cells (47), and it plays a significant role in transendothelial migration of T lymphocytes and monocytes (20 -23). In examining the mechanism by which anti-ICAM-1 Abs may block transepithelial transmission of HIV-1, our results show that in the in vivo HuPBL-SCID mouse model, the binding of the Ab to ICAM-1 on the murine reproductive epithelium is critical for blocking cell-associated transmission.…”

Effect of mifepristone on endometrial matrix metalloproteinase expression and leukocyte abundance in new medroxyprogesterone acetate users

“…However, many women also need protection against unintended pregnancy, and therefore there is demand for the development of dual protection microbicides One non-contraceptive vaginal microbicide under intensive investigation at the Population Council for the prevention of HIV and sexually transmitted infections (STIs) in women is Carraguard (carrageenan PDR98-15: CARRA). Carrageenans have shown antiviral and antibacterial properties against HIV, herpes simplex virus-type 2 (HSV-2) and Neisseria gonorrhoeae [1][2][3][4][5][6]. The safety of vaginal administration has also been confirmed by laboratory and Phase 1 and 2 clinical studies [5,[7][8][9].…”

Vaginal Drug Delivery Systems for HIV Prevention

“…The product was tested for safety and efficacy in vitro in a cell-based model using HIV-1 IIIB (CXCR4 virus) (82) and an explant tissue-based model using HIV-1 BaL (CCR5 virus) (83). Human phase 1 studies for this product have shown that the product is safe to healthy women at low risk for HIV who were sexually abstinent (58), safe and acceptable in HIV-positive women who were sexually abstinent (84), and acceptable by both partners (85).…”