Venkataraman et al.20 demonstrated that anti-HIV activity in CVL can be attributed to multiple cationic peptides, as the removal of cationic components abrogates this activity. Singh et al. and Chen et al.58,59 reported that in lungs and skin, some cationic peptides act synergistically, whereas others cancel each other out and still others have find more no effect on each other. Further studies in the FRT are required to determine the contributions of individual molecules towards

overall anti-HIV activity. As mucosal antimicrobials interact in a very complex manner, it is unlikely that deletion of single molecules would affect the overall antimicrobial activity of the secretions.41,60 What remains to be determined is why, in spite of the presence of Trappin-2/Elafin and other endogenous antiviral molecules, women become infected with HIV. As discussed elsewhere, we have reviewed the literature and concluded that multiple immunological parameters in the upper and lower FRT are suppressed at midcycle, between the time of ovulation and implantation, to optimize the conditions for fertilization and

implantation.28 As a result, we postulate that this website for a 7-day time-period beginning with ovulation, there exists a window of vulnerability when a woman might be more likely to be infected by HIV.28 With specific reference to the innate immune Fossariinae system, we and others have reported that antiviral molecules, including SLPI, defensins, etc., are lowest at this time relative to early

proliferative and late secretory stages of the menstrual cycle.28 It remains to be determined whether nadir levels are below the threshold of immune protection as a result of the direct effects of sex hormones on immune cell synthesis and secretion. Beyond the absolute level of these molecules in CVL, the biological activity of each must also be considered. For example, others have recently reported that kallikreins, a family of serine proteases known for their influence on the development of innate antimicrobial peptide function, are present in FRT secretions.61 As kallikreins vary with stage of the menstrual cycle,62,63 these findings suggest that conversion of inactive molecules to biologically active ones may be as important as the levels of antimicrobials present in FRT secretions. Another processing molecule is the serine protease CD26, which is important for activating chemokines such as stromal derived growth factor-1 (SDF-1) and MIP1β that block the cell-surface receptors required for HIV entry.64,65 Our finding of Trappin-2/Elafin and other antimicrobials being produced and secreted into the lumen by upper FRT cells provides an explanation for what has been a paradoxical observation. It is well established that bacteria reach the upper FRT within minutes of vaginal deposition.