title: A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models.
abstract: Human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2) are the etiologic agents of AIDS. Most HIV-1 infected individuals worldwide are women, who acquire HIV infections during sexual contact. Blocking HIV mucosal transmission and local spread in the female lower genital tract is important in preventing infection and ultimately eliminating the pandemic. Microbicides work by destroying the microbes or preventing them from establishing an infection. Thus, a number of different types of microbicides are under investigation, however, the lack of their solubility and bioavailability, and toxicity has been major hurdles. Herein, we report the development of multifunctional chitosan-lipid nanocomplexes that can effectively deliver plasmids encoding siRNA(s) as microbicides without adverse effects and provide significant protection against HIV in both in vitro and in vivo models. Chitosan or chitosan-lipid (chlipid) was complexed with a cocktail of plasmids encoding HIV-1-specific siRNAs (psiRNAs) and evaluated for their efficacy in HEK-293 cells, PBMCs derived from nonhuman primates, 3-dimensional human vaginal ectocervical tissue (3D-VEC) model and also in non-human primate model. Moreover, prophylactic administration of the chlipid to deliver a psiRNA cocktail intravaginally with a cream formulation in a non-human primate model showed substantial reduction of SHIV (simian/human immunodeficiency virus SF162) viral titers. Taken together, these studies demonstrate the potential of chlipid-siRNA nanocomplexes as a potential genetic microbicide against HIV infections.
authors.affiliation: Department of Internal Medicine -Division of Translational Medicine and Nanomedicine Research Center, University of South Florida, Tampa, Florida, United States of America; Transgenex Nanobiotech Inc, Tampa, Florida, United States of America.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Boyapalle
authors.affiliation: Department of Internal Medicine -Division of Translational Medicine and Nanomedicine Research Center, University of South Florida, Tampa, Florida, United States of America; Transgenex Nanobiotech Inc, Tampa, Florida, United States of America.
authors.forename: Weidong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America; Transgenex Nanobiotech Inc, Tampa, Florida, United States of America.
authors.forename: Payal
authors.initials: P
authors.lastname: Raulji
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America; James A Haley VA Hospital, Tampa, Florida, United States of America.
authors.forename: Subhra
authors.initials: S
authors.lastname: Mohapatra
authors.affiliation: Department of Internal Medicine -Division of Translational Medicine and Nanomedicine Research Center, University of South Florida, Tampa, Florida, United States of America; James A Haley VA Hospital, Tampa, Florida, United States of America.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D015658:HIV Infections / Q000517:prevention & control / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D009092:Mucous Membrane / Q000821:virology; D053761:Nanocomposites / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D011817:Rabbits; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D046509:Tissue Culture Techniques; D014162:Transfection; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering