Highly mutated antibodies capable of neutralizing N276 glycan-deficient HIV after a single immunization with an Env trimer

Lee, Jeong Hyun; Nakao, Catherine; Appel, Michael Y.; Le, Amber; Landais, Elise; Kalyuzhniy, Oleksandr; Hu, Xiaozhen; Liguori, Alessia; Mullen, Tina-Marie; Gröschel, Bettina; Abbott, Robert G.; Sok, Devin; Schief, William R.; Crotty, Shane

doi:10.1016/j.celrep.2022.110485

Cited by 7 publications

(3 citation statements)

References 83 publications

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“… 10 , 11 , 12 , 13 Broadly neutralizing antibodies (NAbs) against pathogens are often highly mutated, having gone through many rounds of SHM and selection. 32 , 33 , 34 , 35 , 36 , 37 However, continued SHM relies on the presence of the antigen in the GCs. 10 , 13 , 38 , 39 , 40 Here, we show that SHM occurs for at least 8 months post vaccination with Ad26.COV2.S, which is longer than expected for a protein and inactivated virus vaccine but has been reported for virus infection and live virus vaccines.…”

Section: Discussionmentioning

confidence: 99%

B cell somatic hypermutation following COVID-19 vaccination with Ad26.COV2.S

Jacob-Dolan,

Lifton,

Powers

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 99%

B cell somatic hypermutation following COVID-19 vaccination with Ad26.COV2.S

Jacob-Dolan,

Lifton,

Powers

et al. 2024

iScience

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“…These antibodies derive from a VH1-2*02 heavy chain and a light chain with a LCDR3 of five amino acids. The vaccine implications of this reproducibility are being explored by germline-targeting approaches in human VH1-2 knock-in mouse models 46–50 and human clinical trials 51 . Other multidonor classes of antibodies include those that use the VH1-69 gene, such as the stem-directed broadly neutralizing antibodies against influenza A virus 52–54 or the CD4-induced class of antibodies that recognize the co-receptor binding site on HIV-1 55 .…”

Section: Discussionmentioning

confidence: 99%

HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

Roark,

Habib,

Gorman

et al. 2024

Preprint

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Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition.HighlightsIsolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaquesCryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognitionAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame twoThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodiesStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition modePropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naïve rhesus repertoireDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity

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“…Strategies to modulate B cell immunodominance will likely be key to inform rational vaccine designs, particularly for difficult pathogens 10 , 11 , 16 . Modifying antigen characteristics (“intrinsic properties”) – antigen affinity and precursor frequency 17 , antigen valency 18 , and quantity of T FH help 19 , 20 –can profoundly impact B cell competitive fitness and composition in the GCs.…”

Section: Introductionmentioning

confidence: 99%

A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates

Phung,

Rodrigues,

Marina-Zárate

et al. 2023

Nat Commun

Self Cite

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Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-TFH cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM BPC) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation.

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Highly mutated antibodies capable of neutralizing N276 glycan-deficient HIV after a single immunization with an Env trimer

Cited by 7 publications

References 83 publications

B cell somatic hypermutation following COVID-19 vaccination with Ad26.COV2.S

B cell somatic hypermutation following COVID-19 vaccination with Ad26.COV2.S

HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates

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