A potential synthetic vaccine that attacks Achilles’ heel of HIV-1

What is it about?

Due to the extremely rapid level of mutation in HIV genomic sequence, and the high degree of variability between viral clades, the majority of the actual vaccine strategy is dedicated to generate broadly neutralizing antibodies. Consequently, a conserved functional sequence in the HIV genome may represent the "Achilles' heel" of HIV-1 for the development of an efficient vaccine.

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Why is it important?

We have previously identified a caveolin-1 binding motif (CBM, 623WNNMTWMEW631) in the ectodomain of HIV-1 transmembrane envelope glycoprotein, gp41, which is conserved in every single HIV-1 isolate. This strong conservation suggests that there is a constant selective pressure to preserve this sequence for a specific HIV function. By a series of studies, we demonstrated that the CBM sequence is required for gp41 translocation within the plasma membrane. We have also reported that synthetic peptides containing the CBM sequence are immunogenic in rodents. Our results published in the September issue of Journal of Virology, demonstrate that macaques immunized with the CBM-based peptides with the adjuvant CpG DNA, displayed a delay in the onset of viral infection and CD4 depletion. This vaccine based on CBM peptides induces a recall memory T-cell response. This recall memory T cell response enforces the potentiality of our vaccine strategy. Moreover, as immune responses against the CBD1-epitope are not detectable in HIV-infected individuals; CBD1-based vaccines could have applications as a therapeutic vaccine in AIDS patients. Publications related to this manuscript Hovanessian AG, Soundaramourty C, Benferhat R, Le Grand R, Dereuddre-Bosquet N, Krust B, Estaquier. 2018. 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. J Virol. 29: (18). pii: e00370-18. doi: 10.1128/JVI.00370-18. Hovanessian AG, Briand J-P, Said EA, Svab J, Ferris S, Dali H, Muller S, Desgranges C, Krust B. 2004. The caveolin-1 binding domain of HIV-1 glycoprotein gp41 is an efficient B cell epitope vaccine candidate against virus infection. Immunity 21:617-627. Rey-Cuillé M, Svab J, Krust B, Briand J, Muller S, Hovanessian A. 2006. The CBD1 epitope is an efficient B-cell epitope vaccine candidate that elicits broadly neutralizing antibodies specific to HIV-1. J Pharm Pharmacol 58:759-767. Benferhat R, Krust B, Rey-Cuille MA, Hovanessian AG. 2009. The caveolin-1 binding domain of HIV-1 glycoprotein gp41 (CBD1) contains several overlapping neutralizing epitopes. Vaccine 27:3620-3630. Benferhat R, Martinon F, Krust B, Le Grand R, Hovanessian AG. 2009. The CBD1 peptide corresponding to the caveolin-1 binding domain of HIV-1 glycoprotein gp41 elicits neutralizing antibodies in cynomolgus macaques when administered with the tetanus T helper epitope. Molecular immunology 46:705-712. Benferhat R, Sanchez-Martinez S, Nieva JL, Briand JP, Hovanessian AG. 2008. The immunogenic CBD1 peptide corresponding to the caveolin-1 binding domain in HIV-1 envelope gp41 has the capacity to penetrate the cell membrane and bind caveolin-1. Molecular immunology 45:1963-1975.

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