Tailored immunogens for rationally designed antibody-based HIV-1 vaccines

Mouquet, Hugo

doi:10.1016/j.it.2015.07.001

Cited by 7 publications

(7 citation statements)

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“…Enormous advances are being made in isolating bnAbs against HIV from patients (10-15), understanding the evolutionary pathways that lead to bnAbs in individuals (23)(24)(25)(26)(27)(28), and developing immunogens to activate the germline B cells that can mature into bnAbs (17)(18)(19)(20)(21)35 (3,6,8,20,22,34). Our past work leading to this conclusion considered variant Ags separated by relatively large mutational distances.…”

Section: Discussionmentioning

confidence: 99%

“…6) followed by sequential immunization with variant Ags separated by a larger mutational distance (3,6,8,20,22,34). Alternatively, the most efficient strategy may be sequential immunization followed by a mixture of variant Ags, as in ref.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma B cells secrete Abs, which are modified forms of the BCR. There is a growing consensus that guiding this Darwinian evolutionary process toward the production of bnAbs will require immunization with an Ag that activates the correct germline B cells (17)(18)(19)(20)(21) followed by multiple variant Ags that share a set of conserved residues and mimic the HIV viral spike (3,6,8,20,22).…”

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confidence: 99%

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Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

Shaffer

Moore

Kardar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags). Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies, suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances may best promote the evolution of bnAbs.HIV | broadly neutralizing antibodies | statistical mechanics | evolutionary biology | biophysics

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

Shaffer

Moore

Kardar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Some Env immunogens, including proteins used in the RV144 trial, are based on a soluble monomeric form of the gp120 subunit of the trimer (1)(2)(3)(4)(5)(6)(7). An alternative approach involves soluble oligomeric gp140 proteins that contain both gp120 and the external component of the gp41 subunit (8)(9)(10)(11)(12)(13). The concept underlying the use of gp140 proteins is that they may better mimic the native virion-associated trimer and hence may be superior to the individual gp120 subunits at inducing virus neutralizing antibodies (NAbs) (8)(9)(10).…”

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confidence: 99%

“…An alternative approach involves soluble oligomeric gp140 proteins that contain both gp120 and the external component of the gp41 subunit (8)(9)(10)(11)(12)(13). The concept underlying the use of gp140 proteins is that they may better mimic the native virion-associated trimer and hence may be superior to the individual gp120 subunits at inducing virus neutralizing antibodies (NAbs) (8)(9)(10). The underlying assumption is now known to be invalid in many cases, since the precise design of the soluble gp140 protein is critical for achieving trimer mimicry (11)(12)(13)(14)(15)(16).…”

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confidence: 99%

Native Conformation and Canonical Disulfide Bond Formation Are Interlinked Properties of HIV-1 Env Glycoproteins

Cupo

Ringe

et al. 2016

J Virol

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We investigated whether there is any association between a native-like conformation and the presence of only the canonical (i.e., native) disulfide bonds in the gp120 subunits of a soluble recombinant human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein. We used a mass spectrometry (MS)-based method to map the disulfide bonds present in nonnative uncleaved gp140 proteins and native-like SOSIP.664 trimers based on the BG505 env gene. Our results show that uncleaved gp140 proteins were not homogeneous, in that substantial subpopulations (20 to 80%) contained aberrant disulfide bonds. In contrast, the gp120 subunits of the native-like SOSIP.664 trimer almost exclusively retained the canonical disulfide bond pattern. We also observed that the purification method could influence the proportion of an Env protein population that contained aberrant disulfide bonds. We infer that gp140 proteins may always contain a variable but substantial proportion of aberrant disulfide bonds but that the impact of this problem can be minimized via design and/or purification strategies that yield native-like trimers. The same factors may also be relevant to the production and purification of monomeric gp120 proteins that are free of aberrant disulfide bonds. IMPORTANCEIt is widely thought that a successful HIV-1 vaccine will include a recombinant form of the Env protein, a trimer located on the virion surface. To increase yield and simplify purification, Env proteins are often made in truncated, soluble forms. A consequence, however, can be the loss of the native conformation concomitant with the virion-associated trimer. Moreover, some soluble recombinant Env proteins contain aberrant disulfide bonds that are not expected to be present in the native trimer. To assess whether these observations are linked, to determine the extent of disulfide bond scrambling, and to understand why scrambling occurs, we determined the disulfide bond profiles of two soluble Env proteins with different designs that are being assessed as vaccine candidates. We found that uncleaved gp140 forms heterogeneous mixtures in which aberrant disulfide bonds abound. In contrast, BG505 SOSIP.664 trimers are more homogeneous, native-like entities that contain predominantly the native disulfide bond profile. The first human immunodeficiency virus type 1 (HIV-1) vaccine trial (designated RV144) to yield one statistically significant measure of efficacy was reported in 2009 (1). Since then, attempts to substantially improve on those initial results have been ongoing. Many vaccine design strategies are focused on the HIV-1 Env protein, which is the trimeric antigen present on the viral surface. Some Env immunogens, including proteins used in the RV144 trial, are based on a soluble monomeric form of the gp120 subunit of the trimer (1-7). An alternative approach involves soluble oligomeric gp140 proteins that contain both gp120 and the external component of the gp41 subunit (8-13). The concept underlying the use of gp140 proteins is that they may ...

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Targeting Glycans on Human Pathogens for Vaccine Design

Krumm

Doores

2018

Current Topics in Microbiology and Immunology

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Glycosylation is an important post-translational modification that is required for structural and stability purposes and functional roles such as signalling, attachment and shielding. Many human pathogens such as bacteria display an array of carbohydrates on their surface that are non-self to the host; others such as viruses highjack the host-cell machinery and present self-carbohydrates sometimes arranged in a non-self more immunogenic manner. In combination with carrier proteins, these glycan structures can be highly immunogenic. During natural infection, glycan-binding antibodies are often elicited that correlate with long-lasting protection. A great amount of research has been invested in carbohydrate vaccine design to elicit such an immune response, which has led to the development of vaccines against the bacterial pathogens Haemophilus influenzae type b, Streptococcus pneumonia and Neisseria meningitidis. Other vaccines, e.g. against HIV-1, are still in development, but promising progress has been made with the isolation of broadly neutralizing glycan-binding antibodies and the engineering of stable trimeric envelope glycoproteins. Carbohydrate vaccines against other pathogens such as viruses (Dengue, Hepatitis C), parasites (Plasmodium) and fungi (Candida) are at different stages of development. This chapter will discuss the challenges in inducing cross-reactive carbohydrate-targeting antibodies and progress towards carbohydrate vaccines.

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Tailored immunogens for rationally designed antibody-based HIV-1 vaccines

Cited by 7 publications

References 10 publications

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

Native Conformation and Canonical Disulfide Bond Formation Are Interlinked Properties of HIV-1 Env Glycoproteins

Targeting Glycans on Human Pathogens for Vaccine Design

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