CoChat
Sign Up
Cited by 25HIV Research and TreatmentMonoclonal and Polyclonal Antibodies ResearchHIV/AIDS drug development and treatment

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration

Open access
Zhu, Linjing, Huang, Bilian, Wang, Xiangyao, Ni, Fengfeng, Ao, Mingjun, Wang, Ruoke, Zheng, Bin, Chen, Chen, Xue, Jing, Zhu, Lin, Yang, Chenbo, Shi, Lingen, Geng, Shengya, Hu, Jiaqian, Yang, Mengshi, Zhang, Doudou, Yang, Ping, Li, Miaomiao, Li, Yuncheng, Hu, Qinxue, Ye, Sheng, Zheng, Peng, Wei, Hongxia, Wu, Zhiwei, Zhang, Linqi, Wang, Yaxin, Liu, Yalan, Wu, Xilin·2024·Nature Communications
DOI 10.1038/s41467-024-51414-6PMC PMC11322561

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Abstract Despite substantial progress in antiretroviral therapy (ART) effectively suppressing HIV-1 replication in the bloodstream, a cure for HIV remains elusive. Existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects, and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, the primary receptor for HIV-1 entry into host cells, was once a prime target for drug or vaccine development. However, challenges, such as the potency and breadth of neutralization and cytotoxicity associated with anti-CD4 antibodies, hindered progress. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignited interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we investigated anti-CD4 nanobodies, with a focus on Nb457 isolated from a human CD4-immunized alpaca. Nb457 displayed remarkable ultra-high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Importantly, Nb457 showed no impact on CD4+ T cell function, akin to Ibalizumab. Strikingly, engineered trimeric Nb457 nanobodies, Nb457-NbHSA-Nb457, achieved 100% inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis revealed that Nb457 binding induced a CD4 conformational change, impeding viral entry. Molecular Dynamics simulations elucidated the structural basis for the complete inhibition of HIV-1 by Nb457-NbHSA-Nb457. Furthermore, Nb457 exhibited significant therapeutic efficacy against HIV-1 infection in humanized mouse models. In conclusion, our study highlights ultra-potent anti-CD4 nanobodies as a compelling source of new HIV-1 therapeutics. The development of Nb457-based drugs holds the potential to revolutionize clinical HIV-1 treatment, providing a powerful tool in the battle against this persistent global health challenge.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-024-51414-6

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. Van de Perre, P. et al. Eliminating postnatal HIV transmission in high incidence areas: need for complementary biomedical interventions. Lancet 397, 1316–1324 (2021). · DOI
  2. Gupta-Wright, A. et al. Virological failure, HIV-1 drug resistance, and early mortality in adults admitted to hospital in Malawi: an observational cohort study. Lancet HIV 7, e620–e628 (2020). · DOI
  3. Gupta, R. K. et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect. Dis. 18, 346–355 (2018). · DOI
  4. Haynes, B. F., Burton, D. R. & Mascola, J. R. Multiple roles for HIV broadly neutralizing antibodies. Sci. Transl. Med. 11, eaaz2686 (2019). · DOI
  5. Caskey, M., Klein, F. & Nussenzweig, M. C. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic. Nat. Med. 25, 547–553 (2019). · DOI
  6. Emu, B. et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N. Engl. J. Med. 379, 645–654 (2018). · DOI
  7. Blair, H. A. Ibalizumab: a review in multidrug-resistant HIV-1 infection. Drugs 80, 189–196 (2020). · DOI
  8. Wu, X. et al. Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice. J. Clin. Invest. 128, 2239–2251 (2018). · DOI
  9. Niu, M. et al. Tandem bispecific antibody prevents pathogenic SHIVSF162P3CN infection and disease progression. Cell Rep. 36, 109611 (2021). · DOI
  10. Hamerscasterman, C. et al. Naturally-occurring antibodies devoid of light-chains. Nature 363, 446–448 (1993). · DOI · Paper page
  11. Jovcevska, I. & Muyldermans, S. The therapeutic potential of nanobodies. Biodrugs 34, 11–26 (2020). · DOI · Paper page
  12. Muyldermans, S. Applications of Nanobodies. Annu Rev Anim Biosci. 9, 401–421 (2021). · DOI
  13. Ji, M. et al. Inhibition of SFTSV replication in humanized mice by a subcutaneously administered anti-PD1 nanobody. EMBO Mol. Med. 16, 575–595 (2024). · DOI
  14. Wu, X. et al. A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration. Cell Rep. 37, 109869 (2021). · DOI
  15. Wu, X. et al. Short-term instantaneous prophylaxis and efficient treatment against SARS-CoV-2 in hACE2 mice conferred by an intranasal nanobody (Nb22). Front. Immunol. 13, 865401 (2022). · DOI
  16. Koenig, P. A. et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science 371, eabe6230 (2021). · DOI
  17. Chen, F., Liu, Z. & Jiang, F. Prospects of neutralizing nanobodies against SARS-CoV-2. Front. Immunol. 12, 690742 (2021). · DOI
  18. Scully, M. et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N. Engl. J. Med. 380, 335–346 (2019). · DOI
  19. Zheng, F. et al. Applications of nanobodies in brain diseases. Front. Immunol. 13, 978513 (2022). · DOI
  20. Traenkle, B. et al. Single-domain antibodies for targeting, detection, and in vivo imaging of human CD4(+) cells. Front. Immunol. 12, 799910 (2021). · DOI
  21. Duan, L. W. et al. A non-canonical binding interface in the crystal structure of HIV-1 gp120 core in complex with CD4. Sci. Rep. 7, 46733 (2017). · DOI
  22. Kwong, P. D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 (1998). · DOI
  23. Freeman, M. M. et al. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody. Structure 18, 1632–1641 (2010). · DOI
  24. Yin, Y., Wang, X. X. & Mariuzza, R. A. Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4. Proc. Natl Acad. Sci. USA 109, 5405–5410 (2012). · DOI
  25. deCamp, A. et al. Global panel of HIV-1 Env reference strains for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol. 88, 2489–2507 (2014). · DOI
  26. Zhou, P. et al. Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies. Plos Pathog. 15, e1007819 (2019). · DOI
  27. Lucas, J. et al. Identification of early-induced broadly neutralizing activities against transmitted founder HIV strains. Aids 37, 43–49 (2023). · DOI
  28. Huang, Y. X. et al. Engineered bispecific antibodies with exquisite HIV-1-neutralizing activity. Cell 165, 1621–1631 (2016). · DOI
  29. Pace, C. S. et al. Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1. Proc. Natl Acad. Sci. USA 110, 13540–13545 (2013). · DOI
  30. Walsh, S. R. & Seaman, M. S. Broadly neutralizing antibodies for HIV-1 prevention. Front. Immunol. 12, 712122 (2021). · DOI
  31. Kwong, P. D., Mascola, J. R. & Nabel, G. J. Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nat. Rev. Immunol. 13, 693–701 (2013). · DOI
  32. Wu, X. et al. A single-domain antibody inhibits SFTSV and mitigates virus-induced pathogenesis in vivo. JCI insight 5, e136855 (2020). · DOI
  33. Wu, X. et al. Induction of neutralizing antibodies by human papillomavirus vaccine generated in mammalian cells. Antib. Ther. 2, 45–53 (2019).
  34. Baral, T. N., MacKenzie, R. & Arbabi Ghahroudi, M. Single-domain antibodies and their utility. Current protocols in immunology/edited by John E. Coligan… [et al.] 103, Unit 2 17, https://doi.org/10.1002/0471142735.im0217s103 (2013). · DOI
  35. Jahnichen, S. et al. CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. Proc. Natl Acad. Sci. USA 107, 20565–20570 (2010). · DOI
  36. Shang, H. et al. Genetic and neutralization sensitivity of diverse HIV-1 env clones from chronically infected patients in China. J. Biol. Chem. 286, 14531–14541 (2011). · DOI
  37. Wu, X. et al. Brain invasion by CD4(+) T cells infected with a transmitted/founder HIV-1BJZS7 during acute stage in humanized mice. J. NeuroImmune Pharmacol. J. Soc. NeuroImmune Pharmacol. 11, 572–583 (2016). · DOI
  38. Minor, W., Cymborowski, M., Otwinowski, Z. & Chruszcz, M. HKL-3000: the integration of data reduction and structure solution - from diffraction images to an initial model in minutes. Acta Crystallogr. Sect. D. -Struct. Biol. 62, 859–866 (2006). · DOI
  39. Mccoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007). · DOI · Paper page
  40. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. Sect. D. -Struct. Biol. 66, 213–221 (2010). · DOI · Paper page
  41. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. Sect. D. -Biol. Crystallogr. 66, 486–501 (2010). · DOI · Paper page
  42. Krissinel, E. & Henrick, K. Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 372, 774–797 (2007). · DOI
  43. Laskowski, R. A. & Swindells, M. B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Modeling 51, 2778–2786 (2011). · DOI
  44. Doyle, C. & Strominger, J. L. Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330, 256–259 (1987). · DOI
  45. Waterhouse, A. et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296–W303 (2018). · DOI
  46. Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017). · DOI
  47. Sanner, M. F., Olson, A. J. & Spehner, J. C. Reduced surface: an efficient way to compute molecular surfaces. Biopolymers 38, 305–320 (1996). · DOI

Metadata

Authors
Zhu, L., Huang, B., Wang, X., Ni, F., Ao, M., Wang, R., Zheng, B., Chen, C., Xue, J., Zhu, L., Yang, C., Shi, L., Geng, S., Hu, J., Yang, M., Zhang, D., Yang, P., Li, M., Li, Y., Hu, Q., Ye, S., Zheng, P., Wei, H., Wu, Z., Zhang, L., Wang, Y., Liu, Y., & Wu, X.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Nanjing University (CN)
  • Tianjin University (CN)
  • Chinese Academy of Sciences (CN)
  • Tsinghua University (CN)
  • Nanjing University of Chinese Medicine (CN)
  • Ningxia University (CN)
  • State Key Laboratory of Analytical Chemistry for Life Science (CN)
Corresponding author
  • Wu, Zhiwei
  • Zhang, Linqi
  • Wang, Yaxin
  • Liu, Yalan
  • Wu, Xilin
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-08-13
Volume
15
Issue
1
Pages
6961-6961
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-51414-6
PMC
PMC11322561
OpenAlex
W4401533531
Cited by
25
References
2
Citations by year
2026: 10 · 2025: 14 · 2024: 1
FWCI
5.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (32370988)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
HIV-1, HIV-1 entry inhibition, broadly neutralizing antibodies, ibalizumab, alpaca immunization, humanized mice
MeSH terms
Broadly Neutralizing Antibodies, Animals, Antibodies, Monoclonal, Camelids, New World, Female, Humans, Models, Molecular, Protein Conformation, HIV Antibodies, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, CD4 Antigens, Protein Structure, Tertiary, Anti-HIV Agents, Protein Structure, Quaternary, Mice, Virus Internalization, Protein Multimerization, Antibodies, Neutralizing, HEK293 Cells, Single-Domain Antibodies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review