HIV-1 vaccine immunogen design strategies

The enormous diversity of HIV-1 is a significant impediment in selecting envelopes (Envs) that can be suitable for designing vaccine immunogens. While tremendous progress has been made in developing soluble, trimeric, native-like Env proteins, those that have elicited neutralizing antibodies (Abs) in animal models are relatively few. A strategy of selecting naturally occurring Envs suitable for immunogen design by studying the correlation between efficient cleavage on the cell surface and their selective binding to broadly neutralizing Abs (bNAbs) and not to non-neutralizing Abs (non-NAbs), properties essential in immunogens, may be useful. Here we discuss some of the challenges of developing an efficacious HIV-1 vaccine and the work done in generating soluble immunogens. We also discuss the study of naturally occurring, membrane-bound, efficiently cleaved (naturally more sensitive to furin) Envs and how they may positively add to the repertoire of HIV-1 Envs that can be used for vaccine immunogen design. However, even with such Envs, the challenges of developing well-folded, native-like trimers as soluble proteins or using other immunogen strategies such as virus-like particles with desirable antigenic properties remain, and are formidable. In spite of the progress that has been made in the HIV-1 vaccine field, an immunogen that elicits neutralizing Abs with significant breadth and potency in vaccines has still not been developed. Efficiently cleaved Envs may increase the number of available Envs suitable for immunogen design and should be studied further.

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Stabilization of Outer Domain of gp120 from HIV-1 Subtype C for Vaccine Immunogen Design

Procedia in Vaccinology ◽

10.1016/j.provac.2015.05.002 ◽

2015 ◽

Vol 9 ◽

pp. 6-15 ◽

Cited By ~ 1

Author(s):

Jesse Thompson ◽

Pankaj Kumar ◽

Jizu Yi ◽

Dane Bowder ◽

Charles Wood ◽

...

Keyword(s):

Subtype C ◽

Vaccine Immunogen ◽

Outer Domain ◽

Immunogen Design ◽

Hiv 1

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HIV-1 Envelope Conformation, Allostery, and Dynamics

Viruses ◽

10.3390/v13050852 ◽

2021 ◽

Vol 13 (5) ◽

pp. 852

Author(s):

Ashley Lauren Bennett ◽

Rory Henderson

Keyword(s):

Host Cell ◽

Conformational Changes ◽

Neutralizing Antibodies ◽

Critical Role ◽

Cell Receptor ◽

Broadly Neutralizing Antibodies ◽

Structural Mapping ◽

Host Cell Receptor ◽

Immunogen Design ◽

Hiv 1

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

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Rationally designed immunogens enable immune focusing to the SARS-CoV-2 receptor binding motif

10.1101/2021.03.15.435440 ◽

2021 ◽

Author(s):

Blake M. Hauser ◽

Maya Sangesland ◽

Kerri St. Denis ◽

Jared Feldman ◽

Evan C. Lam ◽

...

Keyword(s):

Receptor Binding ◽

Viral Entry ◽

Viral Escape ◽

Binding Motif ◽

Design Strategies ◽

Viral Epitope ◽

Viral Glycoproteins ◽

Immunogen Design ◽

Humoral Responses ◽

Serum Response

Eliciting antibodies to surface-exposed viral glycoproteins can lead to protective responses that ultimately control and prevent future infections. Targeting functionally conserved epitopes may help reduce the likelihood of viral escape and aid in preventing the spread of related viruses with pandemic potential. One such functionally conserved viral epitope is the site to which a receptor must bind to facilitate viral entry. Here, we leveraged rational immunogen design strategies to focus humoral responses to the receptor binding motif (RBM) on the SARS-CoV-2 spike. Using glycan engineering and epitope scaffolding, we find an improved targeting of the serum response to the RBM in context of SARS-CoV-2 spike imprinting. Furthermore, we observed a robust SARS-CoV-2-neutralizing serum response with increased potency against related sarbecoviruses, SARS-CoV and WIV1-CoV. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses and represents an adaptable design approach for targeting conserved epitopes on other viral glycoproteins.

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B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study

Nature Biotechnology ◽

10.1038/nbt.2197 ◽

2012 ◽

Vol 30 (5) ◽

pp. 423-433 ◽

Cited By ~ 322

Author(s):

Barton F Haynes ◽

Garnett Kelsoe ◽

Stephen C Harrison ◽

Thomas B Kepler

Keyword(s):

B Cell ◽

Vaccine Development ◽

Cell Lineage ◽

Immunogen Design ◽

Hiv 1

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Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2017.07.044 ◽

2017 ◽

Vol 139 ◽

pp. 865-883 ◽

Cited By ~ 16

Author(s):

Murugaiah A.M. Subbaiah ◽

Nicholas A. Meanwell ◽

John F. Kadow

Keyword(s):

Protease Inhibitors ◽

Design Strategies ◽

Pharmaceutical Properties ◽

Hiv 1

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A Systematic Approach to HIV-1 Vaccine Immunogen Selection

AIDS Research and Human Retroviruses ◽

10.1089/aid.2019.0239 ◽

2020 ◽

Vol 36 (9) ◽

pp. 762-770

Author(s):

Alexander Bontempo ◽

Maria M. Garcia ◽

Naylene Rivera ◽

Mark J. Cayabyab

Keyword(s):

Systematic Approach ◽

Vaccine Immunogen ◽

Hiv 1

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Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers

Journal of Virology ◽

10.1128/jvi.00677-17 ◽

2017 ◽

Vol 91 (15) ◽

Cited By ~ 23

Author(s):

Rajesh P. Ringe ◽

Gabriel Ozorowski ◽

Kimmo Rantalainen ◽

Weston B. Struwe ◽

Katie Matthews ◽

...

Keyword(s):

Animal Models ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Tier 2 ◽

Present Generation ◽

Coreceptor Binding ◽

Tier 1 ◽

Immunogen Design ◽

V3 Region ◽

Hiv 1

ABSTRACT Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes.

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