Abstract
Broadly neutralizing antibodies (bNAbs) targeting conserved regions within the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (Env) can be generated by the human immune system and their elicitation by vaccination will be a key point to protect against the wide range of viral diversity. The membrane proximal external region (MPER) is a highly conserved region within the Env gp41 subunit, plays a major role in membrane fusion and is targeted by naturally induced bNAbs. Therefore, the MPER is considered as an attractive vaccine target. However, despite many attempts to design MPER-based immunogens, further study is still needed to understand its structural complexity, its amphiphilic feature, and its limited accessibility by steric hindrance. These particular features compromise the development of MPER-specific neutralizing responses during natural infection and limit the number of bNAbs isolated against this region, as compared with other HIV-1 vulnerability sites, and represent additional hurdles for immunogen development. Nevertheless, the analysis of MPER humoral responses elicited during natural infection as well as the MPER bNAbs isolated to date highlight that the human immune system is capable of generating MPER protective antibodies. Here, we discuss the recent advances describing the immunologic and biochemical features that make the MPER a unique HIV-1 vulnerability site, the different strategies to generate MPER-neutralizing antibodies in immunization protocols and point the importance of extending our knowledge toward new MPER epitopes by the isolation of novel monoclonal antibodies. This will be crucial for the redesign of immunogens able to skip non-neutralizing MPER determinants.
Highlights
An Apparently Easy Vaccine TargetThe human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (Env) is the sole viral antigen exposed on the virion surface
Env is synthetized as a precursor gp160 glycoprotein that will yield after cleavage a mature complex constituted by the non-covalent association of three gp120 and three gp41 subunits, resulting in a heavily glycosylated trimer of heterodimers [1,2,3,4,5]
The gp41 fusion peptide (FP) inserts into the target cell membrane accounting for a short-life prehairpin fusion intermediate in which both cellular and viral membranes are connected by an extended conformation of gp41
Summary
The human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (Env) is the sole viral antigen exposed on the virion surface. Alpha-helical domains HR1 and HR2 of each gp monomer are folded back together to generate a 6-helix bundle conformation that brings both target cell and viral membranes closer to produce the membrane merge [10, 11] During this process both FP and the membrane proximal external region (MPER) play a crucial role in membrane destabilization [12]. The MPER presents some immunological, physical, and structural, properties that impact directly on its immunogenicity, explaining the lower MPER neutralizing response of HIV-1 infected individuals comparing with other Env vulnerability regions [35, 36] Those include steric hindrance by gp120 and high hydrophobicity that makes the MPER to be partially embedded within the viral membrane [37]. The fact that other Env vulnerability sites have followed a similar path supports the notion that the MPER is still an HIV-1 vaccine target worth exploring [31]
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