HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage

Landais, Elise; Murrell, Ben; Briney, Bryan; Murrell, Sasha; Rantalainen, Kimmo; Berndsen, Zachary T.; Ramos, Alejandra; Wickramasinghe, Lalinda; Smith, Melissa; Eren, Kemal; Val, Natalia de; Wu, Mengyu; Cappelletti, Audrey; Umotoy, Jeffrey C.; Lie, Yolanda; Wrin, Terri; Algate, Paul A.; Chan-Hui, Po-Ying; Karita, Etienne; Ward, Andrew B.; Wilson, Ian A.; Burton, Dennis R.; Smith, Davey M; Pond, Sergei L. Kosakovsky; Poignard, Pascal

doi:10.1016/j.immuni.2017.11.002

Cited by 97 publications

(142 citation statements)

References 72 publications

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“…Within the CAP256-VRC26 lineage, constrained virus escape was associated with reduced infectivity and altered entry kinetics [111]. This observation is consistent with the likelihood that bNAb epitopes are conserved for functional reasons, with escape likely requiring compensatory mutations [97, 110], and suggests that slower viral escape supports the development of bNAbs through prolonged exposure to antigen [96, 97, 110, 111]. This hypothesis is further supported by the demonstration in vaccine studies that extended antigen availability enhances germinal center activity and resulting neutralizing Ab responses [112, 113].…”

Section: The Role Of Viral Variants In Selecting Bnabsmentioning

confidence: 61%

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

2018

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Broadly neutralizing antibodies (bNAbs), able to prevent viral entry by diverse global viruses, are a major focus of HIV vaccine design, with data from animal studies confirming their ability to prevent HIV infection. However, traditional vaccine approaches have failed to elicit these types of antibodies. During chronic HIV infection, a subset of individuals develops bNAbs, some of which are extremely broad and potent. This review describes the immunological and virological factors leading to the development of bNAbs in such “elite neutralizers”. The features, targets and developmental pathways of bNAbs from their precursors have been defined through extraordinarily detailed within-donor studies. These have enabled the identification of epitope-specific commonalities in bNAb precursors, their intermediates and Env escape patterns, providing a template for vaccine discovery. The unusual features of bNAbs, such as high levels of somatic hypermutation, and precursors with unusually short or long antigen-binding loops, present significant challenges in vaccine design. However, the use of new technologies has led to the isolation of more than 200 bNAbs, including some with genetic profiles more representative of the normal immunoglobulin repertoire, suggesting alternate and shorter pathways to breadth. The insights from these studies have been harnessed for the development of optimized immunogens, novel vaccine regimens and improved delivery schedules, which are providing encouraging data that an HIV vaccine may soon be a realistic possibility.

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Section: The Role Of Viral Variants In Selecting Bnabsmentioning

confidence: 61%

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

2018

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“…Lastly, we tested for a coevolutionary signal in our data. Coevolution in sequence data is notoriously hard to establish (Avila-Herrera & Pollard, 2015), and to our knowledge, reports of HIV/Ab coevolution to date have been universally qualitative, with little or no statistical analyses (Bhiman et al, 2015;Bonsignori, Kreider, et al, 2017;Bonsignori et al, 2016;Nicole A. Doria-Rose et al, 2014;Gao et al, 2014;Landais et al, 2017;Liao et al, 2013;MacLeod et al, 2016;Rantalainen et al, 2018). When it comes to claims of coevolution, there are two sources of uncertainty that we have attempted to account for in this study.…”

Section: Discussionmentioning

confidence: 99%

“…However, longitudinal sequence studies of HIV infections tend to either focus on HIV (Feder, Kryazhimskiy, & Plotkin, 2014;Fischer et al, 2010;Henn et al, 2012;Shankarappa et al, 1999;Zanini et al, 2015) or the AbR (Hoehn et al, 2015;Nourmohammad, Otwinowski, Luksza, Mora, & Walczak, 2018;Xueling Wu et al, 2015), but not both. To our knowledge, only three studies have deeply sequenced the AbR along with the autologous HIV population, but each of these studies consisted of a single individual with relatively few time-points (Bhiman et al, 2015;Landais et al, 2017;Liao et al, 2013). In this study, we ameliorate this dearth of data, and describe in unprecedented detail the genetic interaction between these putatively coevolving populations in 10 well-characterized HIVinfected individuals.…”

Section: Introductionmentioning

confidence: 99%

The genetic interaction between HIV and the antibody repertoire

Strauli

Fryer

Pham

et al. 2019

Preprint

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The interaction between human immunodeficiency virus (HIV) and the antibody repertoire (AbR) during chronic infection can provide important information for HIV vaccine research, yet has not been well-characterized on a systems level. We deeply sequenced the HIV population and the AbR of ten HIV-infected, antiretroviral (ART)-naïve individuals, each with 10-20 longitudinal samples spanning 4-14 years. Our unbiased sequencing approach identified partitions of AbRs showing evidence of interaction with autologous HIV populations. We show that these HIV-associated partitions are enriched for the V gene segments of known HIV broadly neutralizing antibodies (bnAbs), indicating that the HIVresponding component of the AbR can be identified via time-series genetic data. Despite this evidence for larger-scale AbR/HIV interactions at the sub-population level, we found little to no evidence for coevolution. This suggests that coevolution is either rare, or hard to detect, which has important vaccine design implications.

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“…An alternative to the cocktail and sequential formulations could be to guide naïve B cell lineages towards bNAb activity by rational design. Since in natural infection the bNAbs develop through the co-evolution of the virus and the antibodies, one strategy that is being pursued is immunization with longitudinal Env sequences from patients that developed a bNAb response [75][76][77][78][79][80]. This strategy aims to recapitulate the evolutionary path of the virus and assumes that the development of the bNAb response largely depends on viral characteristics.…”

Section: Evaluating Env Trimers In Vivo: Learning From Different Immumentioning

confidence: 99%

Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

Peña

Sanders

2018

Retrovirology

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An effective HIV-1 vaccine probably will need to be able to induce broadly neutralizing HIV-1 antibodies (bNAbs) in order to be efficacious. The many bNAbs that have been isolated from HIV-1 infected patients illustrate that the human immune system is able to elicit this type of antibodies. The elucidation of the structure of the HIV-1 envelope glycoprotein (Env) trimer has further fueled the search for Env immunogens that induce bNAbs, but while native Env trimer mimetics are often capable of inducing strain-specific neutralizing antibodies (NAbs) against the parental virus, they have not yet induced potent bNAb responses. To improve the performance of Env trimer immunogens, researchers have studied the immune responses that Env trimers have induced in animals; they have evaluated how to best use Env trimers in various immunization regimens; and they have engineered increasingly stabilized Env trimer variants. Here, we review the different approaches that have been used to increase the stability of HIV-1 Env trimer immunogens with the aim of improving the induction of NAbs. In particular, we draw parallels between the various approaches to stabilize Env trimers and ones that have been used by nature in extremophile microorganisms in order to survive in extreme environmental conditions.

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HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage

Cited by 97 publications

References 72 publications

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

The genetic interaction between HIV and the antibody repertoire

Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

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