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

Gene Therapy volume 21, pages 802–810 (2014)Cite this article

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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.

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Acknowledgements

We thank Dennis Burton (The Scripps Research Institute, La Jolla, CA, USA) for providing the scFv b12DNA plasmid, and Leonidas Stamatatos for providing the SHIV162p4 virus. We thank clinical staff Joshua Kramer, Amber Hoggatt and Matt Beck for veterinary services and Karen Boisvert for microscopy and immunofluorescence assistance. This work was supported by NIH R21/R33 AI079767 (to WAM), by the New England Primate Research Center Base Grant P51OD011103-51 (NEPRC) and the T32 Training Grant T32OD011064 (to SW).

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Authors and Affiliations

  1. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    U M Abdel-Motal, T Han, Q Zhu & W A Marasco

  2. Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA

    C Harbison & S Westmoreland

  3. Department of Obstetrics and Gynecology, School of Medicine, Boston University, Boston, MA, USA

    J Pudney & D J Anderson

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  1. U M Abdel-Motal
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Correspondence to W A Marasco.

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Abdel-Motal, U., Harbison, C., Han, T. et al. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. Gene Ther 21, 802–810 (2014). https://doi.org/10.1038/gt.2014.56

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