Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro

Ussama M. Abdel-Motal, Phuong T N Sarkis, Thomas Han, Jeffery Pudney, Deborah J. Anderson, Quan Zhu, Wayne A. Marasco

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background: Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb) that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS. Methods and Findings: This study tested the hypothesis that adeno-associated virus (AAV)-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc), or "minibody" was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1 bal in an organotypic human vaginal epithelial cell (VEC) model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP. Conclusion: This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles.

Original languageEnglish
Article numbere26473
JournalPLoS One
Volume6
Issue number10
DOIs
Publication statusPublished - 27 Oct 2011
Externally publishedYes

Fingerprint

Gene transfer
female genitalia
Human immunodeficiency virus 1
Neutralizing Antibodies
Viruses
gene transfer
Dependovirus
HIV-1
epithelial cells
Epithelial Cells
viruses
neutralizing antibodies
Genes
Stem cells
HIV Envelope Protein gp120
Viral Envelope Proteins
Single-Chain Antibodies
stem cells
Anti-Infective Agents
Stem Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro. / Abdel-Motal, Ussama M.; Sarkis, Phuong T N; Han, Thomas; Pudney, Jeffery; Anderson, Deborah J.; Zhu, Quan; Marasco, Wayne A.

In: PLoS One, Vol. 6, No. 10, e26473, 27.10.2011.

Research output: Contribution to journalArticle

Abdel-Motal, Ussama M. ; Sarkis, Phuong T N ; Han, Thomas ; Pudney, Jeffery ; Anderson, Deborah J. ; Zhu, Quan ; Marasco, Wayne A. / Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro. In: PLoS One. 2011 ; Vol. 6, No. 10.
@article{db73e3b2f925432d882f3608d5c3d764,
title = "Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro",
abstract = "Background: Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb) that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS. Methods and Findings: This study tested the hypothesis that adeno-associated virus (AAV)-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc), or {"}minibody{"} was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1 bal in an organotypic human vaginal epithelial cell (VEC) model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP. Conclusion: This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles.",
author = "Abdel-Motal, {Ussama M.} and Sarkis, {Phuong T N} and Thomas Han and Jeffery Pudney and Anderson, {Deborah J.} and Quan Zhu and Marasco, {Wayne A.}",
year = "2011",
month = "10",
day = "27",
doi = "10.1371/journal.pone.0026473",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro

AU - Abdel-Motal, Ussama M.

AU - Sarkis, Phuong T N

AU - Han, Thomas

AU - Pudney, Jeffery

AU - Anderson, Deborah J.

AU - Zhu, Quan

AU - Marasco, Wayne A.

PY - 2011/10/27

Y1 - 2011/10/27

N2 - Background: Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb) that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS. Methods and Findings: This study tested the hypothesis that adeno-associated virus (AAV)-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc), or "minibody" was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1 bal in an organotypic human vaginal epithelial cell (VEC) model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP. Conclusion: This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles.

AB - Background: Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb) that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS. Methods and Findings: This study tested the hypothesis that adeno-associated virus (AAV)-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc), or "minibody" was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1 bal in an organotypic human vaginal epithelial cell (VEC) model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP. Conclusion: This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles.

UR - http://www.scopus.com/inward/record.url?scp=80054844916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054844916&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0026473

DO - 10.1371/journal.pone.0026473

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e26473

ER -