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Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes.

Publication ,  Journal Article
Matoba, N; Griffin, TA; Mittman, M; Doran, JD; Alfsen, A; Montefiori, DC; Hanson, CV; Bomsel, M; Mor, TS
Published in: Curr HIV Res
May 2008

CTB-MPR(649-684), a translational fusion protein consisting of cholera toxin B subunit (CTB) and residues 649 684 of gp41 membrane proximal region (MPR), is a candidate vaccine aimed at blocking early steps of HIV-1 mucosal transmission. Bacterially produced CTB MPR(649-684) was purified to homogeneity by two affinity chromatography steps. Similar to gp41 and derivatives thereof, the MPR domain can specifically and reversibly self-associate. The affinities of the broadly-neutralizing monoclonal Abs 4E10 and 2F5 to CTB MPR(649-684) were equivalent to their nanomolar affinities toward an MPR peptide. The fusion protein's affinity to GM1 ganglioside was comparable to that of native CTB. Rabbits immunized with CTB-MPR(649-684) raised only a modest level of anti-MPR(649-684) Abs. However, a prime-boost immunization with CTB-MPR(649-684) and a second MPR(649-684)-based immunogen elicited a more productive anti-MPR(649-684) antibody response. These Abs strongly blocked the epithelial transcytosis of a primary subtype B HIV-1 isolate in a human tight epithelial model, expanding our previously reported results using a clade D virus. The Abs recognized epitopes at the N-terminal portion of the MPR peptide, away from the 2F5 and 4E10 epitopes and were not effective in neutralizing infection of CD4+ cells. These results indicate distinct vulnerabilities of two separate interactions of HIV-1 with human cells - Abs against the C-terminal portion of the MPR can neutralize CD4+-dependent infection, while Abs targeting the MPR's N-terminal portion can effectively block galactosyl ceramide dependent transcytosis. We propose that Abs induced by MPR(649-684)-based immunogens may provide broad protective value independent of infection neutralization.

Duke Scholars

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Published In

Curr HIV Res

DOI

EISSN

1873-4251

Publication Date

May 2008

Volume

6

Issue

3

Start / End Page

218 / 229

Location

Netherlands

Related Subject Headings

  • Virology
  • Recombinant Fusion Proteins
  • Rabbits
  • Peptide Fragments
  • Molecular Sequence Data
  • Immunization
  • Humans
  • HT29 Cells
  • HIV-1
  • HIV Envelope Protein gp41
 

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Matoba, N., Griffin, T. A., Mittman, M., Doran, J. D., Alfsen, A., Montefiori, D. C., … Mor, T. S. (2008). Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes. Curr HIV Res, 6(3), 218–229. https://doi.org/10.2174/157016208784324994
Matoba, Nobuyuki, Tagan A. Griffin, Michele Mittman, Jeffrey D. Doran, Annette Alfsen, David C. Montefiori, Carl V. Hanson, Morgane Bomsel, and Tsafrir S. Mor. “Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes.Curr HIV Res 6, no. 3 (May 2008): 218–29. https://doi.org/10.2174/157016208784324994.
Matoba N, Griffin TA, Mittman M, Doran JD, Alfsen A, Montefiori DC, et al. Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes. Curr HIV Res. 2008 May;6(3):218–29.
Matoba, Nobuyuki, et al. “Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes.Curr HIV Res, vol. 6, no. 3, May 2008, pp. 218–29. Pubmed, doi:10.2174/157016208784324994.
Matoba N, Griffin TA, Mittman M, Doran JD, Alfsen A, Montefiori DC, Hanson CV, Bomsel M, Mor TS. Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes. Curr HIV Res. 2008 May;6(3):218–229.

Published In

Curr HIV Res

DOI

EISSN

1873-4251

Publication Date

May 2008

Volume

6

Issue

3

Start / End Page

218 / 229

Location

Netherlands

Related Subject Headings

  • Virology
  • Recombinant Fusion Proteins
  • Rabbits
  • Peptide Fragments
  • Molecular Sequence Data
  • Immunization
  • Humans
  • HT29 Cells
  • HIV-1
  • HIV Envelope Protein gp41