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Ambrozak, B. a frequency similar to that of controls after prior exposure to BCD and SIVmac251 in subsequent intravaginal computer virus difficulties (= 0.63), despite the potent antiviral properties of BCD, remains to be determined. These results spotlight the unpredictability of antiviral compounds as topical microbicides and suggest that repeated exposures to candidate treatments should be considered for in vivo evaluation. The prevalence of human immunodeficiency computer virus type 1 (HIV-1) contamination is increasing at high rates in women, predominantly through heterosexual transmission, especially in resource-limited settings. Women now comprise nearly 50% of the worldwide prevalence Calcipotriol of HIV/AIDS (41). This rise, in part, may be due to limited utilization of condoms by HIV-infected male sexual partners (7). To help stem Calcipotriol the increasing heterosexual transmission of HIV-1 to women, a number of prophylactic methods are being evaluated, including topically applied formulations of antiviral compounds intended to be applied by women prior to sexual activity. Such a candidate would be a topical microbicide that could prevent HIV-1 transmission by blocking computer virus binding and/or contamination of mucosal target cells or by inactivating the virions. According to the Rockefeller Foundation, a microbicide that is 60% effective against HIV-1 transmission could avert 2.5 million infections and save $2.7 billion in health care costs and $1 billion in economic productivity costs worldwide (30). As of May 2007, eight products were in active clinical trials as anti-HIV-1 microbicide candidates, of which Carraguard and PRO2000 were the only ones in phase III trials (1). These compounds work through a variety of Calcipotriol mechanisms, including formation of a physical barrier; prevention of viral binding, fusion, or absorption to mucosal cells; and inhibition of viral replication. Some of these compounds act nonspecifically against a range of microbes and may also have spermicidal activity. Three of the eight compounds, tenofovir, UC781, and TMC120, take action on lentiviruses by inhibiting reverse transcription of the viral genome after the computer virus enters the cell. A number of microbicide candidates have been evaluated preclinically for the prevention of intravaginal transmission of lentiviruses Calcipotriol in nonhuman primate models. Cellulose acetate phthalate (CAP) (3, 12, 22), 3HP–LG (47), benzalkonium chloride (37), and cyanovirin (39, 40) inhibited intravaginal transmission of simian immunodeficiency computer virus (SIVmac251) in macaques to numerous degrees by nonspecific interference with computer virus binding and/or attachment to cells. Estradiol implants (33) have been shown to thicken the vaginal epithelium in rhesus macaques, effectively inhibiting intravaginal transmission of SIVmac251. Specifically blocking gp120 interactions with receptor/coreceptors by single or multiple neutralizing antibodies administered topically or systemically (23, 28, 45) or by the CCR5 ligands PSC-RANTES or ?2 RANTES (13, 15) was largely effective in prevention of intravaginal SIV/HIV-1 chimeric computer virus (SHIV) transmission. The CCR5 inhibitor CMPD 167 (43, 45, 46), the gp120 binding inhibitor BMS-378806, and the gp41 inhibitor C52L (44) can significantly prevent intravaginal contamination of rhesus macaques when used topically at relatively high concentrations. 2-Hydroxypropyl–cyclodextrin (BCD) inhibits lentiviral contamination by two different mechanisms. First, BCD has been shown to extract cholesterol and, to a lesser extent, phospholipids from mammalian cells (11). Such lipids have been shown to coalesce into lipid raft structures, which are important for HIV access into (21) and release from target cells in vitro (24, 26). BCD appears to disrupt these cellular lipid rafts, preventing productive contamination of cells (18). Rabbit Polyclonal to ARNT Second, BCD has been shown to deplete cholesterol from your envelopes of HIV and SIV virions, disrupting the viral membrane and viral contents and thereby inactivating the computer virus (8, 9, 19). We hypothesized that BCD could be a microbicidal candidate to inhibit intravaginal transmission of HIV by inactivating the cell-associated and cell-free computer virus, as well as by Calcipotriol alteration of the cervicovaginal target cells. BCD (3%) in phosphate-buffered saline (PBS) was shown to efficiently inhibit intravaginal transmission of cell-associated HIV-1 in a SCID-Hu mouse model of contamination (10). Other attractive microbicidal characteristics of BCD were its high solubility in water, its lack of color or odor, and its low cost. In addition, BCD is used extensively as a.