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Immunization with hybrid proteins containing the membrane proximal external region of HIV-1.

ABSTRACT: The transmembrane envelope (TM) protein gp41 of HIV-1 is an attractive target when designing a vaccine to induce neutralizing antibodies. A few broadly neutralizing antibodies (2F5, 4E10, and 10E8) that target conserved epitopes in the membrane proximal external region (MPER) of gp41 have been isolated from infected individuals. However, attempts to induce such antibodies by immunizations with gp41 and Env derivatives containing the MPER were successful only to some extent. In contrast, immunizations with the ectodomain of the TM protein p15E of different gamma retroviruses resulted in the induction of neutralizing antibodies. These sera recognized epitopes located in the MPER and in the fusion peptide proximal region (FPPR) of p15E. Based on these results, both regions of p15E were substituted with the corresponding sequences derived from gp41 of HIV-1. Thus, four different hybrid antigens were produced. One of the inserted sequences contained the epitopes of 2F5 and 4E10 in the MPER; the other corresponded to the FPPR. Vaccination of rats, guinea pigs, and a goat induced binding antibodies directed against the FPPR of gp41 and the 2F5 epitope (ELDKWA) located in the MPER. Despite the exact recognition of the 2F5 epitope, no or very weak neutralization of HIV-1NL4-3 by the immune sera was demonstrated. Nonetheless, using the strategy of hybrid proteins, antibodies targeting the desired epitope were successfully induced.

SUBMITTER: Strasz N

PROVIDER: S-EPMC4010167 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Immunization with hybrid proteins containing the membrane proximal external region of HIV-1.

Strasz Nicola N Morozov Vladimir A VA Kreutzberger Jürgen J Keller Martina M Eschricht Magdalena M Denner Joachim J

AIDS research and human retroviruses 20140207 5

The transmembrane envelope (TM) protein gp41 of HIV-1 is an attractive target when designing a vaccine to induce neutralizing antibodies. A few broadly neutralizing antibodies (2F5, 4E10, and 10E8) that target conserved epitopes in the membrane proximal external region (MPER) of gp41 have been isolated from infected individuals. However, attempts to induce such antibodies by immunizations with gp41 and Env derivatives containing the MPER were successful only to some extent. In contrast, immuniza ...[more]

PMID: 24392780

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Project description:The membrane proximal external region (MPER) is a highly conserved membrane-active region located at the juxtamembrane positions within class I viral fusion glycoproteins and essential for membrane fusion events during viral entry. The MPER in the human immunodeficiency virus type I (HIV-1) envelope protein (Env) interacts with the lipid bilayers through a cluster of tryptophan (Trp) residues and a C-terminal cholesterol-interacting motif. The inclusion of the MPER N-terminal sequence contributes to the membrane reactivity and anti-viral efficacy of the first two anti-HIV peptidyl fusion inhibitors T20 and T1249. As a type I transmembrane protein, Env also interacts with the cellular membranes during its biosynthesis and trafficking. Here we investigated the roles of MPER membrane-active sequences during both viral entry and assembly, specifically, their roles in the design of peptidyl fusion inhibitors and the biosynthesis of viral structural proteins. We found that elimination of the membrane-active elements in MPER peptides, namely, penta Trp→alanine (Ala) substitutions and the disruption of the C-terminal cholesterol-interacting motif through deletion inhibited the anti-viral effect against the pseudotyped HIV-1. Furthermore, as compared to C-terminal dimerization, N-terminal dimerization of MPER peptides and N-terminal extension with five helix-forming residues enhanced their anti-viral efficacy substantially. The secondary structure study revealed that the penta-Trp→Ala substitutions also increased the helical content in the MPER sequence, which prompted us to study the biological relevance of such mutations in pre-fusion Env. We observed that Ala mutations of Trp664, Trp668 and Trp670 in MPER moderately lowered the intracellular and intraviral contents of Env while significantly elevating the content of another viral structural protein, p55/Gag and its derivative p24/capsid. The data suggest a role of the gp41 MPER in the membrane-reactive events during both viral entry and budding, and provide insights into the future development of anti-viral therapeutics.

Dataset Information

Immunization with hybrid proteins containing the membrane proximal external region of HIV-1.

Publications

Immunization with hybrid proteins containing the membrane proximal external region of HIV-1.

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