Transcytosis-Blocking Abs Elicited by an Oligomeric Immunogen Based on the Membrane Proximal Region of HIV-1 gp41 Target Non-Neutralizing Epitopes

Title: Transcytosis-Blocking Abs Elicited by an Oligomeric Immunogen Based on the Membrane Proximal Region of HIV-1 gp41 Target Non-Neutralizing Epitopes

Volume: 6 Issue: 3

Author(s): Nobuyuki Matoba, Tagan A. Griffin, Michele Mittman, Jeffrey D. Doran, Annette Alfsen, David C. Montefiori, Carl V. Hanson, Morgane Bomsel and Tsafrir S. Mor

Affiliation:

Keywords: HIV vaccine, mucosal transmission, functional non-neutralizing antibodies, prime/boost, transcytosis

Abstract: CTB-MPR649-684, 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-MPR649-684 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-MPR649-684 were equivalent to their nanomolar affinities toward an MPR peptide. The fusion proteins affinity to GM1 ganglioside was comparable to that of native CTB. Rabbits immunized with CTB-MPR649-684 raised only a modest level of anti-MPR649-684 Abs. However, a prime-boost immunization with CTB-MPR649-684 and a second MPR649-684-based immunogen elicited a more productive anti-MPR649-684 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 MPRs N-terminal portion can effectively block galactosyl ceramide dependent transcytosis. We propose that Abs induced by MPR649-684-based immunogens may provide broad protective value independent of infection neutralization.

Cite this article as:

Matoba Nobuyuki, Griffin A. Tagan, Mittman Michele, Doran D. Jeffrey, Alfsen Annette, Montefiori C. David, Hanson V. Carl, Bomsel Morgane and Mor S. Tsafrir, Transcytosis-Blocking Abs Elicited by an Oligomeric Immunogen Based on the Membrane Proximal Region of HIV-1 gp41 Target Non-Neutralizing Epitopes, Current HIV Research 2008; 6 (3) . https://dx.doi.org/10.2174/157016208784324994