This application is in response to the NIH RFA (DE-03-002) entitled """"""""Oral Mucosal Innate Immune Factors in the Inhibition of HIV and Opportunistic Infections."""""""" Specifically, we will study a novel factor of the oral innate immunity--mannose-binding lectin (MBL)--of commensal bacteria. ? ? The rationale is that the human MBL binds and neutralizes HIV, but it exists only in serum, not on mucosal surfaces where most HIV infections occur. We think that the lack of host MBL on mucosal surfaces can be compensated, at least in part, by MBL-like lectins of commensal bacteria. Our preliminary studies showed that some lactobacilli that colonize the oral cavity produce moderate levels of MBL-like lectin. Like the human MBL, microbial MBL-like lectins also bind HIV because the HIV receptor, gpl20, is rich in mannose-residues. Lactobacilli, which naturally grow in milk (lacto=milk), are earliest colonizers of the oral and intestinal mucosa in milk-fed infants and are a beginning component of the infant's innate immunity against infectious diseases, such as diarrhea. However, the affinity of microbial MBL-Iike lectins are not high enough to block HIV infections. We hypothesize that oral lactobacilli that produce abundant MBL-like lectins with a high affinity against HIV can be isolated from spontaneously occurred and/or induced mutants. We will obtain these super-MBL lactobacilli by pursuing two specific aims: ? ? 1) Obtain super-MBL Lactobacillus strains by screening spontaneously occurred and/or induced mutants. ? 2) Test the ability of super-MBL lactobacilli to block HIV viruses in vitro ? ? Upon completion of this study, we will have obtained a collection of super-MBL oral lactobacilli that bind and neutralize HIV with high efficiency. These bacteria will be used for further studies on their binding characteristics, safety, in vivo efficacy and colonization in animals and ultimately in human volunteers. The long-term goal of this project is to select food-grade commensal bacteria that naturally trap and kill HIV viruses and to develop a bioprophylactic therapy to safely block the vertical transmission of HIV via breastfeeding. ? ?
