Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

Bonsignori, Mattia; Kreider, Edward F.; Fera, Daniela; Meyerhoff, Robert; Bradley, Todd; Wiehe, Kevin; Alam, S. Munir; Aussedat, Baptiste; Walkowicz, William E.; Hwang, Kwan‐Ki; Saunders, Kevin O.; Zhang, Ruijun; Gladden, Morgan A.; Monroe, Anthony; Kumar, Amit; Xia, Shi-Mao; Cooper, Melissa; Louder, Mark K.; McKee, Krisha; Bailer, Robert T.; Pier, Brendan W.; Jette, C.A.; Kelsoe, Garnett; Williams, Wilton B.; Morris, Lynn; Kappes, John C.; Wagh, Kshitij; Kamanga, Gift; Cohen, Myron S.; Hraber, Peter; Montefiori, David C.; Trama, Ashley M.; Liao, Hua‐Xin; Kepler, Thomas B.; Moody, M. Anthony; Gao, Feng; Danishefsky, Samuel J.; Mascola, John R.; Shaw, George M.; Hahn, Beatrice H.; Harrison, Stephen C.; Korber, Bette T.; Haynes, Barton F.

doi:10.1126/scitranslmed.aai7514

Cited by 243 publications

(428 citation statements)

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“…V3-glycan bnAbs develop in HIV-1-infected individuals only after years of infection (Bonsignori et al, 2017; Doria-Rose et al, 2009; Gray et al, 2011; MacLeod et al, 2016; Sather et al, 2009; Simek et al, 2009; Simonich et al, 2016). We asked if vaccination over a long duration of time with an Env immunogen with N301 and N332 high mannose glycans (Figure S1A and S1B; Go et al, 2008; Liao et al, 2013b) could elicit glycan-dependent antibodies.…”

Section: Resultsmentioning

confidence: 99%

Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates

et al. 2017

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Summary Induction of broadly neutralizing antibodies (bnAbs) that target HIV-1 envelope (Env) is a goal of HIV-1 vaccine development. A bnAb target is the Env third variable loop (V3)-glycan site. To determine if immunization could induce antibodies to the V3-glycan bnAb binding site, we repetitively immunized macaques over a three-year period with an Env expressing V3-high mannose glycans. Env immunizations elicited plasma antibodies that neutralized HIV-1 expressing only high mannose glycans– a characteristic shared by early bnAb B cell lineage members. A rhesus recombinant monoclonal antibody from a vaccinated macaque bound to the V3-glycan site at the same amino acids as broadly neutralizing antibodies. A structure of the antibody bound to glycan revealed the three variable heavy chain complementarity determining regions formed a cavity into which glycan could insert and neutralized multiple HIV-1 isolates with high mannose glycans. Thus, HIV-1 Env vaccination induced mannose-dependent antibodies with characteristics of V3-glycan bnAb precursors.

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Section: Resultsmentioning

confidence: 99%

Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates

et al. 2017

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“…These include the PCDN [59], DH270 [102] and PCIN39 [122] bNAb lineages, further suggesting that shorter maturation pathways more compatible with vaccination can be achieved for this epitope. Furthermore, three of these V3-glycan lineages also achieved breadth without insertion/deletions (indels) in CDR loops, seen as another major roadblock for vaccination.…”

Section: Are the Unusual Features Of Bnabs An Insurmountable Hurdle Fmentioning

confidence: 99%

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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“…Studies of antibody-HIV co-evolution in single individuals who made bnAbs after infection have provided insights into how bnAbs develop (Bonsignori et al, 2017a; Bonsignori et al, 2016; Doria-Rose et al, 2014; Gao et al, 2014; Liao et al, 2013a; MacLeod et al, 2016; Simonich et al, 2016). African individual CH505 developed two different CD4bs bnAbs, CH235.12 and CH103 (Bonsignori et al, 2016; Gao et al, 2014; Liao et al, 2013a).…”

Section: Introductionmentioning

confidence: 99%

Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

Saunders

Verkoczy

Jiang³

et al. 2017

Cell Reports

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SUMMARY The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof-of-concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knock-in mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s. Our results show Env vaccination can elicit broad neutralization of tier 2 HIV-1, demonstrate V1V2 glycan bnAbs are more readily induced than CD4bs bnAbs, and define VH replacement and diversity region fusion as potential mechanisms for generating V1V2-glycan bnAb site antibodies.

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Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

Cited by 243 publications

References 50 publications

Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates

Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates

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

Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

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