The development of HIV vaccines targeting gp41 membrane-proximal external region (MPER): challenges and prospects

Huan Liu,Lu Lu,Xiaojie Su,Lulu Si,Shibo Jiang

doi:10.1007/s13238-018-0534-7

Abstract

A human immunodeficiency virus type-1 (HIV-1) vaccine which is able to effectively prevent infection would be the most powerful method of extinguishing pandemic of the acquired immunodeficiency syndrome (AIDS). Yet, achieving such vaccine remains great challenges. The membrane-proximal external region (MPER) is a highly conserved region of the envelope glycoprotein (Env) gp41 subunit near the viral envelope surface, and it plays a key role in membrane fusion. It is also the target of some reported broadly neutralizing antibodies (bNAbs). Thus, MPER is deemed to be one of the most attractive vaccine targets. However, no one can induce these bNAbs by immunization with immunogens containing the MPER sequence(s). The few attempts at developing a vaccine have only resulted in the induction of neutralizing antibodies with quite low potency and limited breadth. Thus far, vaccine failure can be attributed to various characteristics of MPER, such as those involving structure and immunology; therefore, we will focus on these and review the recent progress in the field from the following perspectives: (1) MPER structure and its role in membrane fusion, (2) the epitopes and neutralization mechanisms of MPER-specific bNAbs, as well as the limitations in eliciting neutralizing antibodies, and (3) different strategies for MPER vaccine design and current harvests.

Highlights

Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV) infection, which can impair and even destroy the human immune system
The RV144 vaccine trial that was launched in Thailand in 2009 is the only clinical trial showing an efficacy of 31.2% reduction of HIV type 1 (HIV-1) infection (Kim et al, 2015), and since no more effective human immunodeficiency virus type-1 (HIV-1) vaccine has been developed
Similar to 4E10, the crystal structure of Fab 10E8 in complex with its epitope peptide forms an α helical conformation (Huang et al, 2012). These results indicated that membrane-proximal external region (MPER) is natively flexible, indicating that more than one structure is associated with neutralization and, at the same time, implying that multiple conformations of MPER immunogens may be favorable to the induction of broadly neutralizing antibodies (bNAbs)

Summary

INTRODUCTION

Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV) infection, which can impair and even destroy the human immune system. Luo et al (2006) utilized P15 of porcine endogenous retrovirus to replace E2 region with MPER, and the antiserum could neutralize HIV pseudoviruses at 1:20 When it comes to modified HIV-1 Env, such as replacing the loop between NHR and CHR with 2F5 epitope directly (Vassell et al, 2015), replacing the loop with GGGGS sequence (Habte et al, 2015), or deleting the cleavage site of gp120 and gp and fusion peptide (Dennison et al, 2011), antibodies without neutralizing activity were all detected in different kinds of antisera immunized with these modified proteins. The serum from immunized rabbits had MPER-specific antibodies, but without neutralizing activity

Design of immunogens

CONCLUSIONS AND PROSPECTS

Findings

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