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The Structural and Immunological Properties of Chimeric Proteins Containing HIV-1 MPER Sites.

ABSTRACT: The human immunodeficiency virus (HIV-1) poses a serious risk to global public health. The development of a safe and effective vaccine could stop the HIV/AIDS pandemic. Much of the research focused on HIV-1 prevention through vaccination is aimed at developing immunogens and immunization strategies to induce the formation of antibodies with neutralizing activity against a broad range of HIV-1 isolates (bNAbs). The objective of this study was to develop immunogens capable of targeting an immune response to MPER, one of the regions of bNAb binding in Env. Two immunogens carrying MPER fragments on their scaffolds (protein YkuJ Bacillus subtilis and artificial polypeptide TBI) were constructed. Circular dichroism spectroscopy was used to show that the secondary structure of the immunogens was consistent with their theoretical models. The antigenic structure of the MPER-TBI and YkuJ-MPER proteins was characterized using bNAbs that recognize HIV-1 MPER (2F5, 4E10, and 10E8). The rabbit model made it possible to show the immunogenicity of the constructed recombinant proteins. The resulting serum was found to be cross-reactive with immunogens carrying MPER. The constructs designed and characterized in this study can be used for targeting the humoral immune response to MPER, which is known to be one of the sites of HIV-1 vulnerability.

SUBMITTER: Rudometov AP

PROVIDER: S-EPMC6826149 | biostudies-literature | 2019 Jul-Sep

REPOSITORIES: biostudies-literature

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The Structural and Immunological Properties of Chimeric Proteins Containing HIV-1 MPER Sites.

Rudometov A P AP Rudometova N B NB Shcherbakov D N DN Lomzov A A AA Kaplina O N ON Shcherbakova N S NS Ilyichev A A AA Bakulina A Yu AY Karpenko L I LI

Acta naturae 20190701 3

The human immunodeficiency virus (HIV-1) poses a serious risk to global public health. The development of a safe and effective vaccine could stop the HIV/AIDS pandemic. Much of the research focused on HIV-1 prevention through vaccination is aimed at developing immunogens and immunization strategies to induce the formation of antibodies with neutralizing activity against a broad range of HIV-1 isolates (bNAbs). The objective of this study was to develop immunogens capable of targeting an immune r ...[more]

PMID: 31720017

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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

The Structural and Immunological Properties of Chimeric Proteins Containing HIV-1 MPER Sites.

Publications

The Structural and Immunological Properties of Chimeric Proteins Containing HIV-1 MPER Sites.

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