title: Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer.
abstract: Topical microbicides are a leading strategy for prevention of HIV mucosal infection to women; however, numerous pharmacokinetic limitations associated with coitally related dosing strategy have contributed to their limited success. Here we test the hypothesis that adeno-associated virus (AAV) mediated delivery of the b12 human anti-HIV-1 gp120 minibody gene to the lower genital tract of female rhesus macaques (Rh) can provide prolonged expression of b12 minibodies in the cervical-vaginal secretions. Gene transfer studies demonstrated that, of various green fluorescent protein (GFP)-expressing AAV serotypes, AAV-6 most efficiently transduced freshly immortalized and primary genital epithelial cells (PGECs) of female Rh in vitro. In addition, AAV-6-b12 minibody transduction of Rh PGECs led to inhibition of SHIV162p4 transmigration and virus infectivity in vitro. AAV-6-GFP could also successfully transduce vaginal epithelial cells of Rh when applied intravaginally, including p63+ epithelial stem cells. Moreover, intravaginal application of AAV-6-b12 to female Rh resulted in prolonged minibody detection in their vaginal secretions throughout the 79-day study period. These data provide proof of principle that AAV-6-mediated delivery of anti-HIV broadly neutralizing antibody (BnAb) genes to the lower genital tract of female Rh results in persistent minibody detection for several months. This strategy offers promise that an anti-HIV-1 genetic microbicide strategy may be possible in which topical application of AAV vector, with periodic reapplication as needed, may provide sustained local BnAb expression and protection.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: U M
authors: UM
authors: Abdel-Motal
authors: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA.
authors: C
authors: C
authors: Harbison
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: T
authors: T
authors: Han
authors: Department of Obstetrics and Gynecology, School of Medicine, Boston University, Boston, MA, USA.
authors: J
authors: J
authors: Pudney
authors: Department of Obstetrics and Gynecology, School of Medicine, Boston University, Boston, MA, USA.
authors: D J
authors: DJ
authors: Anderson
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Q
authors: Q
authors: Zhu
authors: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA.
authors: S
authors: S
authors: Westmoreland
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: W A
authors: WA
authors: Marasco
mesh_terms: D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology*; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D005836:Genitalia, Female / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D015483:HIV Antibodies / Q000235:genetics / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008253:Macaca mulatta / Q000378:metabolism / Q000821:virology*
chemical_list: D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120