Abstract
Purpose of reviewTo provide an update on the latest developments in the field of HIV-1 antibody-based soluble envelope glycoprotein (Env) trimer design for vaccine use.Recent findingsThe development of soluble native-like HIV-1 Env trimer immunogens has moved the field of antibody-based vaccine design forward dramatically over the past few years with refinement of various stabilizing approaches. However, despite this progress, significant challenges remain. Firstly, although trimers are relatively stable in solution, they nevertheless sample different conformational states, some of which may be less relevant to binding and induction of broadly neutralizing antibodies (bNAbs). Secondly, these trimers expose unwanted immunodominant surfaces that may distract the adaptive immune response from recognizing more immunorecessive but conserved neutralization-relevant surfaces on the trimer. The availability of atomic-resolution structural information has allowed guided design of mutations that have further stabilized trimers and allowed reduced exposure of unwanted epitopes. Moreover, chemical cross-linking approaches that do not require structural information have also contributed to trimer stabilization and selection of particular conformational forms. However, current knowledge suggests that strategies additional to trimer stabilization will be required to elicit bNAb, including targeting naïve B cell receptors with specific immunogens, and guiding B cell lineages toward recognizing conserved surfaces on Env with high affinity.SummaryThis review will give a perspective on these challenges, and summarize current approaches to overcoming them with the aim of developing immunogens to elicit bNAb responses in humans by active vaccination.
Highlights
An effective HIV-1 vaccine is expected to require the induction of protective antibodies, most probably neutralizing antibodies (NAbs)
The concept that NAbs might form the basis for a protective vaccine against HIV-1 infection was first tested in nonhuman primates (NHPs), and revealed that gp120based immunogens elicited antibody responses that neutralized homologous virus and protected NHPs from challenge [1]
This led to the concept of conformational stabilization of the closed conformation by two approaches: mutagenesis based on structure-guided design, and chemical cross-linking
Summary
An effective HIV-1 vaccine is expected to require the induction of protective antibodies, most probably neutralizing antibodies (NAbs). In parallel came realization that antibodies elicited by immunization with gp120 only weakly engaged gp120 on the surface of virions or infected cells in the context of the functional viral envelope aDepartment of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, bDepartment of Microbiology and Immunology, Weill Medical College of Cornell University, New York, USA and cSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK. HIV and novel strategies for induction of broad neutralizing antibodies following vaccination
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