The human immunodeficiency virus (HIV) and herpes simplex virus (HSV) cause significant morbidity and mortality. While both viruses can be transmitted sexually, people with genital herpes are more prone to HIV. Condoms offer excellent protection, but the effect has been limited due to poor compliance. Alternative prophylaxis, such as microbicides, for use by women are desirable. HIV is an RNA virus, while HSV is a DNA virus, but they both have an envelope with high mannose. Coincidentally, certain lactobacilli naturally capture mannose as a preferred nutrient by a specific binding protein-dependent sugar uptake system. Its sugar-binding protein (lectin) binds mannose. By screening nearly 1,000 oral and vaginal strains for such lectin, we have selected two strains from oral and five from vaginal lactobacilli that can capture and metabolize envelope mannose of HIV/HSV. Therefore, we propose to develop a probiotic microbicide against both HIV and HSV based on Lactobacillus mannose-binding lectin (LMBL). We hypothesize that LMBL+ lactobacilli can block both HIV and HSV infections by mannose-specific binding. This project is to perform preclinical studies. We will pursue five specific aims: (1) phenotypic and genotypic analyses of candidate LMBL+ lactobacilli; (2) document blockage of LMBL+ lactobacilli against HSV-2 and HIV-1 in vitro; (3) test anti-HSV-2 efficacy of LMBL+ lactobacilli in vivo in a mouse herpes model; (4) assess safety of LMBL+ lactobacilli in vivo in rabbits and rats; and (5) optimize formulation, packaging, and shelf life of the probiotic microbicide. Upon completion of this study, we will achieve preclinical data and be ready for clinical trials. Putative advantages of this method include safety, persistent protection and cost-efficiency. Superior to all other, microbicides, the new method can be compliance-independent. It can protect women unobtrusively and inconspicuously. Our long-term goal is to develop a bio-prophylaxis that can serve as an alternative or supplement to vaccines or physical barriers to protect women against sexual transmission of HIV and HSV. We propose to develop a novel method to fight AIDS and herpes viruses with their natural enemies. We have isolated a group of friendly lactobacilli, which can capture viruses for their sugar, thereby killing the virus, much like cats catching mice. Successful development of this method will likely curb the global HIV/HSV pandemic and ultimately save many lives. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI066709-04
Application #
7456591
Study Section
Special Emphasis Panel (ZAI1-HSD-M (M2))
Program Officer
Deal, Carolyn D
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$490,858
Indirect Cost
Name
University of Illinois at Chicago
Department
Dentistry
Type
Schools of Dentistry
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Gravett, Michael G; Jin, Ling; Pavlova, Sylvia I et al. (2012) Lactobacillus and Pediococcus species richness and relative abundance in the vagina of rhesus monkeys (Macaca mulatta). J Med Primatol 41:183-90
Tao, Lin; Pavlova, Sylvia I; Ji, Xin et al. (2011) A novel plasmid for delivering genes into mammalian cells with noninvasive food and commensal lactic acid bacteria. Plasmid 65:8-14
Celigoy, Jessica; Ramirez, Benjamin; Tao, Lin et al. (2011) Probing the HIV gp120 envelope glycoprotein conformation by NMR. J Biol Chem 286:23975-81
Jin, L; Hinde, K; Tao, L (2011) Species diversity and relative abundance of lactic acid bacteria in the milk of rhesus monkeys (Macaca mulatta). J Med Primatol 40:52-8
Sen, Jayita; Yan, Tianran; Wang, Jizhen et al. (2010) Alanine scanning mutagenesis of HIV-1 gp41 heptad repeat 1: insight into the gp120-gp41 interaction. Biochemistry 49:5057-65