Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer

Ussama M. Abdel-Motal, C. Harbison, T. Han, J. Pudney, D. J. Anderson, Q. Zhu, S. Westmoreland, W. A. Marasco

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)802-810
Number of pages9
JournalGene Therapy
Volume21
Issue number9
DOIs
Publication statusPublished - 11 Sep 2014
Externally publishedYes

Fingerprint

Dependovirus
Macaca mulatta
HIV-1
Genes
Epithelial Cells
Green Fluorescent Proteins
Neutralizing Antibodies
Local Anti-Infective Agents
Anti-Infective Agents
HIV Infections
Stem Cells
Pharmacokinetics
HIV
Viruses

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Medicine(all)

Cite this

Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. / Abdel-Motal, Ussama M.; Harbison, C.; Han, T.; Pudney, J.; Anderson, D. J.; Zhu, Q.; Westmoreland, S.; Marasco, W. A.

In: Gene Therapy, Vol. 21, No. 9, 11.09.2014, p. 802-810.

Research output: Contribution to journalArticle

Abdel-Motal, UM, Harbison, C, Han, T, Pudney, J, Anderson, DJ, Zhu, Q, Westmoreland, S & Marasco, WA 2014, 'Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer', Gene Therapy, vol. 21, no. 9, pp. 802-810. https://doi.org/10.1038/gt.2014.56
Abdel-Motal, Ussama M. ; Harbison, C. ; Han, T. ; Pudney, J. ; Anderson, D. J. ; Zhu, Q. ; Westmoreland, S. ; Marasco, W. A. / Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. In: Gene Therapy. 2014 ; Vol. 21, No. 9. pp. 802-810.
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