Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Schommers, Philipp; Gruell, Henning; Abernathy, Morgan E.; Tran, My-Kim; Dingens, Adam S.; Gristick, Harry B.; Barnes, Christopher O.; Schoofs, Till; Schlotz, Maike; Vanshylla, Kanika; Kreer, Christoph; Weiland, Daniela; Holtick, Udo; Scheid, Christof; Valter, Markus M.; Gils, Marit J. van; Sanders, Rogier W.; Vehreschild, Jörg Janne; Cornely, Oliver A.; Lehmann, Clara; Fätkenheuer, Gerd; Seaman, Michael S.; Bloom, Jesse D; Björkman, Pamela J.; Klein, Florian

doi:10.1016/j.cell.2020.01.010

Cited by 118 publications

(172 citation statements)

References 132 publications

(182 reference statements)

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“…Indeed, we combined our escape maps with selections on spike-expressing viruses to show that cocktails of antibodies that compete for binding to spike but have different escape mutations still resist viral escape. It is possible that such cocktails could even be preferable to cocktails of antibodies targeting distinct regions (Schmidt et al, 2015;Schommers et al, 2020) , since acquiring multiple different escape mutations in the ACE2 binding interface could impose an intolerable loss of receptor binding on the virus.…”

Section: Discussionmentioning

confidence: 99%

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

Greaney

Starr

Gilchuk

et al. 2020

Preprint

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448

807

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Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and make a major contribution to the neutralizing antibody response elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding, and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same RBD surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies, and enable us to design escape-resistant antibody cocktails–including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.

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Section: Discussionmentioning

confidence: 99%

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

Greaney

Starr

Gilchuk

et al. 2020

Preprint

Self Cite

448

807

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“…The following bNAbs were tested for neutralizing activity against the PBMC isolates in TZM-bl assays: 3BNC117-LS, VRC01, VRC07-523LS, and 1-18, all of which are CD4 binding sitespecific (CD4bs), (Scheid et al, 2011;Wu et al, 2010;Rudicell et al, 2014;Schommers et al, 2020); 10-1074-LS, and BG18, which target base of the V3 loop and surrounding glycans (Mouquet et al, 2012;Freund et al, 2017); and PGDM1400 and CAP256-VRC25.26, which are specific for the V2 loop (Sok et al, 2014;Doria-Rose et al, 2016). We also tested the combination of 3BNC117-LS and 10-1074-LS, which is currently in clinical development (Mendoza et al, 2018; Bar-On et al, 2018;Cohen et al, 2019) (clinicaltrials.gov/ct2/show/NCT03254277, clinicaltrials.gov/ct2/show/NCT03554408, clinicaltrials.gov/ct2/show/NCT04250636, and clinicaltrials.gov/ct2/show/NCT04173819).…”

Section: Resultsmentioning

confidence: 99%

“…(a). IC50 titer (µg/ml) of unique PBMC-derived viruses (Pr) shown in color, and corresponding clade pseudovirus panel in black (data obtained from the Antibody database software(West et al, 2013); CATNAP(Yoon et al, 2015); ,(Freund et al, 2017);(Schommers et al, 2020) and(Kong et al, 2015) (Pv). The viruses are organized by HIV-1 clade.…”

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confidence: 99%

Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against primary African isolates

Lorenzi

Mendoza

Cohen

et al. 2020

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Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Broadly neutralizing human antibodies (bNAbs) with exceptional activity against HIV-1 are currently being tested in HIV-1 prevention trials. The selection of anti-HIV-1 bNAbs for clinical development was primarily guided by their in vitro neutralizing activity against HIV-1 Env pseudotyped viruses. Here we report on the neutralizing activity of 9 anti-HIV-1 bNAbs now in clinical development against 126 Clade A, C, D PBMC-derived primary African isolates. The neutralizing potency and breadth of the bNAbs tested was significantly reduced compared to pseudotyped viruses panels. The difference in sensitivity between pseudotyped viruses and primary isolates varied from 3-to nearly 100-fold depending on the bNAb and the HIV-1 clade. Thus, the neutralizing activity of bNAbs against primary African isolates differs and cannot be predicted from their activity against pseudovirus panels. The data have significant implications for interpreting the results of ongoing HIV-1 prevention trials.

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“…Indeed, efforts are ongoing to identify bNAbs, including in the VRC01 class, that are less vulnerable to such resistance. 66 For bNAb therapies that target maintenance of HIV remission post ART cessation during chronic infection, our study prescribes the requisite genetic barrier to resistance, i.e. , the number of mutations HIV-1 must accumulate to develop significant resistance to the therapy.…”

Section: Discussionmentioning

confidence: 99%

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

Saha

Dixit

2020

Preprint

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16Broadly neutralizing antibodies (bNAbs) of HIV-1 hold promise of eliciting long-term HIV-1 17 remission. Surprisingly, the bNAb VRC01, when administered concomitantly with the cessation 18 of successful antiretroviral therapy (ART), failed rapidly in chronic HIV-1 patients. We 19 hypothesized that the failure was due to VRC01-resistant strains that were formed before ART 20 initiation, survived ART in latently infected cells, and were reactivated during VRC01 therapy. 21 Current assay limitations preclude testing this hypothesis experimentally. We developed a 22 mathematical model based on the hypothesis and challenged it with available clinical data. The 23 model integrated within-host HIV-1 evolution, stochastic latency reactivation and viral dynamics 24 with multiple dose VRC01 pharmacokinetics. With a virtual patient population, model predictions 25 quantitatively captured data from two independent clinical trials. Accordingly, we attributed 26 VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral 27 recrudescence, particularly during trough VRC01 levels. Accounting for pre-existing resistance 28 may help bNAb therapies maximize HIV-1 remission. 29 30 Antiretroviral therapy (ART) for HIV-1 infection rapidly suppresses viremia to 32 undetectable levels and curtails disease progression but is unable to eradicate the virus. 1 33 Discontinuation of ART, even long after viremic control is established, typically leads to rapid 34 viral rebound, often within days to weeks of discontinuation, and to progressive disease. 2 The 35 rebound is caused by a reservoir of latently infected cells 3 that is formed soon after infection 4 . The 36 reservoir is sustained by cell proliferation 5,6 , which can continue even when ART has stopped new 37 infections, allowing the reservoir to exist long-term 7 . The reservoir can get reactivated 38 stochastically and reignite infection once ART is stopped 8,9 . ART must therefore be administered 39 lifelong. In a remarkable breakthrough, the VISCONTI study showed that when ART is 40 administered early in infection, some individuals can maintain viremic control for many years after 41 the cessation of ART 10 . This study has raised hopes of a functional cure, or long-term remission, 42 of HIV-1, where the viremic control once established by ART can be maintained without lifelong 43 treatment 11 . The success of ART in inducing post-treatment control, however, is small: only ~5-44 15% of the patients treated achieve lasting post-treatment control 12 . Enormous efforts are 45 underway to improve this success rate 11 . 46 One strategy that holds promise is to administer broadly neutralizing antibodies (bNAbs) 47 of HIV-1 for a short period post-ART, i.e., during an analytical treatment interruption (ATI) 13,14 . 48 bNAbs target diverse viral genomic variants 15,16 , and are expected to suppress viremia arising from 49 the reactivation of latently infected cells 17,18 . Simultaneously, they may engage the host immune 50 system 19 , ...

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Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Cited by 118 publications

References 132 publications

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against primary African isolates

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

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