Vaccination with the Conserved Caveolin-1 Binding Motif in Human Immunodeficiency Virus Type 1 Glycoprotein gp41 Delays the Onset of Viral Infection and Provides Partial Protection in Simian/Human Immunodeficiency Virus-Challenged Cynomolgus Macaques

Abstract

We have previously reported that the CBD1 peptide (SLEQIWNNMTWMQWDK), corresponding to the consensus caveolin-1 binding domain in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, elicits peptide-specific antibodies. Here, we have investigated the cellular immune response and the protective efficacy against a simian/human immunodeficiency virus (SHIV) challenge. In addition to the CBD1 peptide, peptides overlapping the caveolin-binding-motif (CBM) (IWNNMTWMQW or IWNNMTW) were fused to a Gag-p24 T helper epitope for vaccination. All immunized cynomolgus macaques responded to a cocktail peptide immunization by inducing specific T cells and the production of high-titer CBD1/CBM peptide-specific antibodies. Six months after the fourth vaccine boost, six control and five vaccinated animals were challenged weekly by repeated exposure to SHIV via the mucosal rectal route. All control animals were infected after 1 to 3 challenges with SHIV, while among the five vaccinated monkeys, three became infected after a delay compared to control; one was infected after the eighth viral challenge, and one remained uninfected even after the ninth SHIV challenge. Immunized animals maintained a CD4 T cell count, and their central memory CD4 T cells were less depleted than in the control group. Furthermore, SHIV challenge stimulates antigen-specific memory T cell response in vaccinated macaques. Our results indicate that peptides derived from the CBM region can be immunogenic and provide protection against SHIV infection in cynomolgus monkeys. In HIV-1-producing cells, gp41 exists in a complexed form with caveolin-1, an interaction most probably mediated by the caveolin-1 binding motif. This sequence is highly conserved in every single HIV-1 isolate, thus suggesting that there is constant selective pressure to preserve this sequence for a specific function in the HIV infectious cycle. Consequently, the CBM sequence may represent the "Achilles' heel" of HIV-1 in the development of an efficient vaccine. Our results demonstrate that macaques immunized with the CBM-based peptides displayed a delay in the onset of viral infection and CD4 depletion, as well as a significant induction of antigen-specific memory T cell response, which is essential for the control of HIV/SIV infections. Finally, as HIV-infected individuals lack anti-CBM immune responses, CBM-based vaccines could have applications as a therapeutic vaccine in AIDS patients.

New GMP manufacturing processes to obtain thermostable HIV-1 gp41 virosomes under solid forms for various mucosal vaccination routes

“…The conserved gp41 that mediates the fusion process with the target cell membrane displays the membrane proximal ectodomain region, which is a highly conserved region recognized by broadly binding neutralizing IgG antibodies (bNAbs) 35,36 like the 2F5 [37][38][39] , 4E10 37,[40][41][42] , or 10E8 43,44 . Other gp41 conserved neutralizing epitopes have been reported, such as the caveoline-1 binding motif 45 or the QARILAV 46 sequence recognized by serum IgA from HIV-1 highly exposed persistently seronegative (HEPS) subjects. There are also other gp41 epitopes that have induced antibodies with the ability to block HIV-1 transcytosis [47][48][49] and support the antibody-dependent cellular cytotoxicity activity 50,51 .…”