Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The HIV-1 envelope glycoprotein: structure, function and interactions with neutralizing antibodies

Nature Reviews Microbiology volume 23, pages 734–752 (2025)Cite this article

Subjects

Abstract

To end the AIDS pandemic, an effective vaccine is sought to prevent new infections by inducing broadly active HIV-1 neutralizing antibodies. Monoclonal neutralizing antibodies can be administered therapeutically to people living with HIV-1 and preventively to those who are uninfected and at risk. Neutralizing antibodies block viral entry into susceptible cells by targeting the HIV-1 envelope glycoprotein, which mediates entry by membrane fusion. The envelope glycoprotein evades neutralizing antibody responses by multiple means, including extreme sequence variation and a dense protective glycan shield. Despite these impediments, many broadly active neutralizing human antibodies have been isolated, typically after years of HIV-1 infection. In this Review, we describe how such antibodies target distinct epitope clusters that cumulatively now cover most of the external surface of the envelope glycoprotein. These antibodies vary in potency, in the degree to which they reduce infectivity, in mechanism of action, and in structural basis, affinity and kinetics of binding. Broadly neutralizing antibody responses have, however, so far not been elicited by immunization with envelope glycoproteins. That situation may change though with the rapid advancement of structure-guided immunogen design strategies that engage germline versions of human antibodies and guide their maturation towards greater neutralization potency and breadth.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sequence and structure of BG505 Env.
Fig. 2: The function of Env in HIV-1 entry.
Fig. 3: The cumulative bnAb epitope area on HIV-1 Env.
Fig. 4: Examples of bnAb–Env trimer complexes representing each epitope cluster.
Fig. 5: A scheme for sequential vaccination to induce bnAbs.

Similar content being viewed by others

References

  1. Joint United Nations Programme on HIV/AIDS. Global HIV & AIDS Statistics — Fact Sheet (UNAIDS, 2024).

  2. Haynes, B. F. et al. Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies. Nat. Rev. Immunol. 23, 142–158 (2023). One of the most recent comprehensive reviews of HIV-1 bnAb induction.

    Article  CAS  PubMed  Google Scholar 

  3. Burton, D. R. Antiviral neutralizing antibodies: from in vitro to in vivo activity. Nat. Rev. Immunol. 23, 720–734 (2023). A recent comprehensive reivew of virus neutralization and other antiviral effects of antibodies; it contains references about the definition and mechanisms of neutralization.

    Article  CAS  PubMed  Google Scholar 

  4. Klasse, P. J., Ozorowski, G., Sanders, R. W. & Moore, J. P. Env exceptionalism: why are HIV-1 Env glycoproteins atypical immunogens? Cell Host Microbe 27, 507–518 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kwong, P. D. & Mascola, J. R. HIV-1 vaccines based on antibody identification, B cell ontogeny, and epitope structure. Immunity 48, 855–871 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Klasse, P. J. & Moore, J. P. Reappraising the value of HIV-1 vaccine correlates of protection analyses. J. Virol. 96, e0003422 (2022).

    Article  CAS  PubMed  Google Scholar 

  7. Klein, F. et al. Antibodies in HIV-1 vaccine development and therapy. Science 341, 1199–1204 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Plotkin, S. A. Recent updates on correlates of vaccine-induced protection. Front. Immunol. 13, 1081107 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Checkley, M. A., Luttge, B. G. & Freed, E. O. HIV-1 envelope glycoprotein biosynthesis, trafficking, and incorporation. J. Mol. Biol. 410, 582–608 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ward, A. B. & Wilson, I. A. The HIV-1 envelope glycoprotein structure: nailing down a moving target. Immunol. Rev. 275, 21–32 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Klasse, P. J. The molecular basis of HIV entry. Cell Microbiol. 14, 1183–1192 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. West, A. P. Jr. et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156, 633–648 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Korber, B. et al. Evolutionary and immunological implications of contemporary HIV-1 variation. Br. Med. Bull. 58, 19–42 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Robert-Guroff, M., Reitz, M. S. Jr., Robey, W. G. & Gallo, R. C. In vitro generation of an HTLV-III variant by neutralizing antibody. J. Immunol. 137, 3306–3309 (1986).

    Article  CAS  PubMed  Google Scholar 

  15. Weiss, R. A. et al. Variable and conserved neutralization antigens of human immunodeficiency virus. Nature 324, 572–575 (1986).

    Article  CAS  PubMed  Google Scholar 

  16. Klein, F. et al. Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153, 126–138 (2013). Pioneering elucidation of the unusual mutations acquired by bnAbs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Scheid, J. F. et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636–640 (2009). A central study in the breakthrough of monoclonal bnAb discoveries.

    Article  CAS  PubMed  Google Scholar 

  18. Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walker, L. M. et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009). A central study in the breakthrough of bnAb discoveries.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Parsons, M. S. et al. Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques. J. Clin. Invest. 129, 182–191 (2019).

    Article  PubMed  Google Scholar 

  21. Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl Acad. Sci. USA 109, 18921–18925 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schommers, P. et al. Restriction of HIV-1 escape by a highly broad and potent neutralizing antibody. Cell 180, 471–489.e22 (2020). This study expands the classes of CD4bs bNAbs of the most impressive breadth and potency; it contains the highest-resolution Env structure and addresses the differential propensity for viral escape from bnAbs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sanders, R. W. & Moore, J. P. Progress on priming HIV-1 immunity. Science 384, 738–739 (2024).

    Article  CAS  PubMed  Google Scholar 

  24. Upadhyay, C. et al. Signal peptide of HIV-1 envelope modulates glycosylation impacting exposure of V1V2 and other epitopes. PLoS Pathog. 16, e1009185 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yolitz, J. et al. Signal peptide of HIV envelope protein impacts glycosylation and antigenicity of gp120. Proc. Natl Acad. Sci. USA 115, 2443–2448 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Haffar, O. K., Dowbenko, D. J. & Berman, P. W. Topogenic analysis of the human immunodeficiency virus type 1 envelope glycoprotein, gp160, in microsomal membranes. J. Cell Biol. 107, 1677–1687 (1988).

    Article  CAS  PubMed  Google Scholar 

  27. Behrens, A. J. & Crispin, M. Structural principles controlling HIV envelope glycosylation. Curr. Opin. Struct. Biol. 44, 125–133 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pritchard, L. K. et al. Structural constraints determine the glycosylation of HIV-1 envelope trimers. Cell Rep. 11, 1604–1613 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Leonard, C. K. et al. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J. Biol. Chem. 265, 10373–10382 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Gristick, H. B. et al. Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat. Struct. Mol. Biol. 23, 906–915 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stewart-Jones, G. B. et al. Trimeric HIV-1-Env structures define glycan shields from clades A, B, and G. Cell 165, 813–826 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Go, E. P. et al. Glycosylation site-specific analysis of clade C HIV-1 envelope proteins. J. Proteome Res. 8, 4231–4242 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cao, L. et al. Global site-specific N-glycosylation analysis of HIV envelope glycoprotein. Nat. Commun. 8, 14954 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Go, E. P., Hua, D. & Desaire, H. Glycosylation and disulfide bond analysis of transiently and stably expressed clade C HIV-1 gp140 trimers in 293 T cells identifies disulfide heterogeneity present in both proteins and differences in O-linked glycosylation. J. Proteome Res. 13, 4012–4027 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McCune, J. M. et al. Endoproteolytic cleavage of gp160 is required for the activation of human immunodeficiency virus. Cell 53, 55–67 (1988).

    Article  CAS  PubMed  Google Scholar 

  36. Ringe, R. P. et al. Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. Proc. Natl Acad. Sci. USA 110, 18256–18261 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pancera, M. et al. Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Nature 514, 455–461 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Julien, J. P. et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342, 1477–1483 (2013). The crystal structure of the Env trimer underpins much of the knowledge we now have about its antigenicity and immunogenicity.

    Article  CAS  PubMed  Google Scholar 

  39. Lyumkis, D. et al. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342, 1484–1490 (2013). The cryo-EM structure of the trimer was concordant with the crystal structure co-published by Julien et al. (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Modrow, S. et al. Computer-assisted analysis of envelope protein sequences of seven human immunodeficiency virus isolates: prediction of antigenic epitopes in conserved and variable regions. J. Virol. 61, 570–578 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Starcich, B. R. et al. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS. Cell 45, 637–648 (1986).

    Article  CAS  PubMed  Google Scholar 

  42. Leszczynski, J. F. & Rose, G. D. Loops in globular proteins: a novel category of secondary structure. Science 234, 849–855 (1986).

    Article  CAS  PubMed  Google Scholar 

  43. Kwon, Y. D. et al. Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc. Natl Acad. Sci. USA 109, 5663–5668 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kwon, Y. D. et al. Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nat. Struct. Mol. Biol. 22, 522–531 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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). The 3D struture of monomeric gp120 is determined and details of interactions with CD4 is revealed by crystallography.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Diskin, R. et al. Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334, 1289–1293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee, J. H. et al. A broadly neutralizing antibody targets the dynamic HIV Envelope trimer apex via a long, rigidified, and anionic β-hairpin structure. Immunity 46, 690–702 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee, J. H., Ozorowski, G. & Ward, A. B. Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer. Science 351, 1043–1048 (2016). This cryo-EM study obtains the 3D structure of membrane-anchored Env trimer without stabilizing mutations in complex with a Fab to the gp120–gp41 interface; it also give the details of glycans and the binding of an MPER Fab.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ozorowski, G. et al. Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike. Nature 547, 360–363 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pancera, M. et al. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc. Natl Acad. Sci. USA 107, 1166–1171 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Rizzuto, C. D. et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280, 1949–1953 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Wyatt, R. et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393, 705–711 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Wyatt, R. & Sodroski, J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280, 1884–1888 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Bartesaghi, A., Merk, A., Borgnia, M. J., Milne, J. L. & Subramaniam, S. Prefusion structure of trimeric HIV-1 envelope glycoprotein determined by cryo-electron microscopy. Nat. Struct. Mol. Biol. 20, 1352–1357 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huang, C. C. et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317, 1930–1934 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu, J., Bartesaghi, A., Borgnia, M. J., Sapiro, G. & Subramaniam, S. Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zanetti, G., Briggs, J. A., Grunewald, K., Sattentau, Q. J. & Fuller, S. D. Cryo-electron tomographic structure of an immunodeficiency virus envelope complex in situ. PLoS Pathog. 2, e83 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zhu, P. et al. Electron tomography analysis of envelope glycoprotein trimers on HIV and simian immunodeficiency virus virions. Proc. Natl Acad. Sci. USA 100, 15812–15817 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dam, K. A., Fan, C., Yang, Z. & Bjorkman, P. J. Intermediate conformations of CD4-bound HIV-1 Env heterotrimers. Nature 623, 1017–1025 (2023). The effects of ligating one, two or three CD4 molecules to the Env trimer are explored by cryo-EM: more than one is needed to open the trimer and trigger major conformational changes; one CD4 molecule bound partly induces an intermediate state.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kong, L. et al. Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120. Nat. Struct. Mol. Biol. 20, 796–803 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li, W. et al. HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes. Nature 623, 1026–1033 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sanders, R. W. et al. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 9, e1003618 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kumar, S. et al. Capturing the inherent structural dynamics of the HIV-1 envelope glycoprotein fusion peptide. Nat. Commun. 10, 763 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Behrens, A. J. et al. Composition and antigenic affects of individual glycan sites of a trimeric HIV-1 Envelope glycoprotein. Cell Rep. 14, 2695–2706 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ringe, R. P. et al. Glycan heterogeneity as a cause of the persistent fraction in HIV-1 neutralization. PLoS Pathog. 19, e1011601 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cao, L. et al. Differential processing of HIV envelope glycans on the virus and soluble recombinant trimer. Nat. Commun. 9, 3693 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Struwe, W. B. et al. Site-specific glycosylation of virion-derived HIV-1 Env is mimicked by a soluble trimeric immunogen. Cell Rep. 24, 1958–1966.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Behrens, A. J. et al. Molecular architecture of the cleavage-dependent mannose patch on a soluble HIV-1 envelope gycoprotein trimer. J. Virol. 91, e01894-16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Go, E. P. et al. Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry. J. Virol. 85, 8270–8284 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chohan, B. et al. Selection for human immunodeficiency virus type 1 envelope glycosylation variants with shorter V1–V2 loop sequences occurs during transmission of certain genetic subtypes and may impact viral RNA levels. J. Virol. 79, 6528–6531 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Derdeyn, C. A. et al. Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science 303, 2019–2022 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Gnanakaran, S. et al. Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections. PLoS Pathog. 7, e1002209 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rizzuto, C. D. & Sodroski, J. G. Contribution of virion ICAM-1 to human immunodeficiency virus infectivity and sensitivity to neutralization. J. Virol. 71, 4847–4851 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ugolini, S. et al. Inhibition of virus attachment to CD4+ target cells is a major mechanism of T cell line-adapted HIV-1 neutralization. J. Exp. Med. 186, 1287–1298 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang, Y. J. et al. Envelope-dependent, cyclophilin-independent effects of glycosaminoglycans on human immunodeficiency virus type 1 attachment and infection. J. Virol. 76, 6332–6343 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gallo, S. A. et al. The HIV Env-mediated fusion reaction. Biochim. Biophys. Acta 1614, 36–50 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Ladinsky, M. S. et al. Electron tomography visualization of HIV-1 fusion with target cells using fusion inhibitors to trap the pre-hairpin intermediate. eLife 9, e58411 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Buzon, V. et al. Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions. PLoS Pathog. 6, e1000880 (2010). This study provides the most advanced knowledge of the post-fusion gp41 structure.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Daecke, J., Fackler, O. T., Dittmar, M. T. & Krausslich, H. G. Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry. J. Virol. 79, 1581–1594 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Miyauchi, K., Kim, Y., Latinovic, O., Morozov, V. & Melikyan, G. B. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell 137, 433–444 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Herold, N. et al. HIV-1 entry in SupT1-R5, CEM-ss, and primary CD4+ T cells occurs at the plasma membrane and does not require endocytosis. J. Virol. 88, 13956–13970 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sharma, M., Marin, M., Wu, H., Prikryl, D. & Melikyan, G. B. Human immunodeficiency virus 1 preferentially fuses with pH-neutral endocytic vesicles in cell lines and human primary CD4+ T-cells. ACS Nano 17, 17436–17450 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, H., Barnes, C. O., Yang, Z., Nussenzweig, M. C. & Bjorkman, P. J. Partially open HIV-1 Envelope structures exhibit conformational changes relevant for coreceptor binding and fusion. Cell Host Microbe 24, 579–592.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, H. et al. Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop. Proc. Natl Acad. Sci. USA 113, E7151–E7158 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yang, Z. et al. Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer. Nat. Commun. 13, 732 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Guttman, M. et al. CD4-induced activation in a soluble HIV-1 Env trimer. Structure 22, 974–984 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Weissenhorn, W., Dessen, A., Harrison, S. C., Skehel, J. J. & Wiley, D. C. Atomic structure of the ectodomain from HIV-1 gp41. Nature 387, 426–430 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Chan, D. C., Fass, D., Berger, J. M. & Kim, P. S. Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263–273 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Bennett, A. L. et al. Microsecond dynamics control the HIV-1 Envelope conformation. Sci. Adv. 10, eadj0396 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cale, E. M. et al. Antigenic analysis of the HIV-1 envelope trimer implies small differences between structural states 1 and 2. J. Biol. Chem. 298, 101819 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stadtmueller, B. M. et al. DEER spectroscopy measurements reveal multiple conformations of HIV-1 SOSIP envelopes that show similarities with envelopes on native virions. Immunity 49, 235–246.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bennett, A. L. & Henderson, R. HIV-1 envelope conformation, allostery, and dynamics. Viruses 13, 852 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Klasse, P. J. Modeling how many envelope glycoprotein trimers per virion participate in human immunodeficiency virus infectivity and its neutralization by antibody. Virology 369, 245–262 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Magnus, C., Rusert, P., Bonhoeffer, S., Trkola, A. & Regoes, R. R. Estimating the stoichiometry of human immunodeficiency virus entry. J. Virol. 83, 1523–1531 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Regoes, R. R. & Magnus, C. The role of chance in primate lentiviral infectivity: from protomer to host organism. Prog. Mol. Biol. Transl. Sci. 129, 327–351 (2015).

    Article  PubMed  Google Scholar 

  97. Anokhin, B. & Spearman, P. Viral and host factors regulating HIV-1 envelope protein trafficking and particle incorporation. Viruses 14, 1729 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mangala Prasad, V. et al. Cryo-ET of Env on intact HIV virions reveals structural variation and positioning on the Gag lattice. Cell 185, 641–653.e17 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Murakami, T., Ablan, S., Freed, E. O. & Tanaka, Y. Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity. J. Virol. 78, 1026–1031 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chojnacki, J. et al. Maturation-dependent HIV-1 surface protein redistribution revealed by fluorescence nanoscopy. Science 338, 524–528 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Jiang, J. & Aiken, C. Maturation of the viral core enhances the fusion of HIV-1 particles with primary human T cells and monocyte-derived macrophages. Virology 346, 460–468 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Davis, M. R., Jiang, J., Zhou, J., Freed, E. O. & Aiken, C. A mutation in the human immunodeficiency virus type 1 Gag protein destabilizes the interaction of the envelope protein subunits gp120 and gp41. J. Virol. 80, 2405–2417 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Piai, A. et al. Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein. Nat. Commun. 11, 2317 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Piai, A. et al. NMR model of the entire membrane-interacting region of the HIV-1 fusion protein and its perturbation of membrane morphology. J. Am. Chem. Soc. 143, 6609–6615 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Murphy, R. E., Samal, A. B., Vlach, J. & Saad, J. S. Solution structure and membrane interaction of the cytoplasmic tail of HIV-1 gp41 protein. Structure 25, 1708–1718.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Salimi, H. et al. The lipid membrane of HIV-1 stabilizes the viral envelope glycoproteins and modulates their sensitivity to antibody neutralization. J. Biol. Chem. 295, 348–362 (2020).

    Article  CAS  PubMed  Google Scholar 

  107. Klasse, P. J. Neutralization of virus infectivity by antibodies: old problems in new perspectives. Adv. Biol. 2014, 157895 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Mouquet, H. et al. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature 467, 591–595 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mouquet, H., Warncke, M., Scheid, J. F., Seaman, M. S. & Nussenzweig, M. C. Enhanced HIV-1 neutralization by antibody heteroligation. Proc. Natl Acad. Sci. USA 109, 875–880 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. McEwan, W. A. & James, L. C. TRIM21-dependent intracellular antibody neutralization of virus infection. Prog. Mol. Biol. Transl. Sci. 129, 167–187 (2015).

    Article  PubMed  Google Scholar 

  111. Yasmeen, A. et al. Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits. Retrovirology 11, 41 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Colin, P. et al. Conformational antigenic heterogeneity as a cause of the persistent fraction in HIV-1 neutralization. Retrovirology 20, 9 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. McCoy, L. E. et al. Incomplete neutralization and deviation from sigmoidal neutralization curves for HIV broadly neutralizing monoclonal antibodies. PLoS Pathog. 11, e1005110 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Pritchard, L. K. et al. Glycan microheterogeneity at the PGT135 antibody recognition site on HIV-1 gp120 reveals a molecular mechanism for neutralization resistance. J. Virol. 89, 6952–6959 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Falkowska, E. et al. Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40, 657–668 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kim, A. S., Leaman, D. P. & Zwick, M. B. Antibody to gp41 MPER alters functional properties of HIV-1 Env without complete neutralization. PLoS Pathog. 10, e1004271 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Weiss, J. N. The Hill equation revisited: uses and misuses. FASEB J. 11, 835–841 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Yoon, H. et al. CATNAP: a tool to compile, analyze and tally neutralizing antibody panels. Nucleic Acids Res. 43, W213–W219 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Binley, J. M. et al. Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies. J. Virol. 78, 13232–13252 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bures, R. et al. Regional clustering of shared neutralization determinants on primary isolates of clade C human immunodeficiency virus type 1 from South Africa. J. Virol. 76, 2233–2244 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Walker, B. D. The AMP trials — a glass half full. N. Engl. J. Med. 384, 1068–1069 (2021).

    Article  PubMed  Google Scholar 

  123. Pegu, A. et al. A meta-analysis of passive immunization studies shows that serum-neutralizing antibody titer associates with protection against SHIV challenge. Cell Host Microbe 26, 336–346.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Glogl, M. et al. Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization. Nat. Struct. Mol. Biol. 30, 1323–1336 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lee, J. H. et al. Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike. Nat. Commun. 6, 8167 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Chuang, G. Y. et al. Structural survey of broadly neutralizing antibodies targeting the HIV-1 Env trimer delineates epitope categories and characteristics of recognition. Structure 27, 196–206.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. Dingens, A. S., Arenz, D., Weight, H., Overbaugh, J. & Bloom, J. D. An Antigenic atlas of HIV-1 escape from broadly neutralizing antibodies distinguishes functional and structural epitopes. Immunity 50, 520–532.e3 (2019). A prominent study based on the new method of deep mutational scanning applied to bnAb epitopes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Radford, C. E. et al. Mapping the neutralizing specificity of human anti-HIV serum by deep mutational scanning. Cell Host Microbe 31, 1200–1215.e9 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gaebler, C. et al. Prolonged viral suppression with anti-HIV-1 antibody therapy. Nature 606, 368–374 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. LaMont, C. et al. Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1. eLife 11, e76004 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Doria-Rose, N. A. et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509, 55–62 (2014). Among the first papers to report on the ontogeny of bnAbs, setting the scene for germline-targeting strategies for their induction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bonsignori, M. et al. Maturation pathway from germline to broad HIV-1 neutralizer of a CD4-mimic antibody. Cell 165, 449–463 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Landais, E. et al. HIV Envelope glycoform heterogeneity and localized diversity govern the initiation and maturation of a V2 apex broadly neutralizing antibody lineage. Immunity 47, 990–1003.e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Liao, H. X. et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469–476 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Umotoy, J. et al. Rapid and focused maturation of a VRC01-class HIV broadly neutralizing antibody lineage involves both binding and accommodation of the N276-glycan. Immunity 51, 141–154.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Moore, P. L. et al. Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nat. Med. 18, 1688–1692 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kwong, P. D. et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678–682 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Sok, D. et al. The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. PLoS Pathog. 9, e1003754 (2013). Pioneering identification of the unusual mutations acquired by a bnAb family.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Yin, Y. et al. In vivo affinity maturation of mouse B cells reprogrammed to express human antibodies. Nat. Biomed. Eng. 8, 361–379 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kepler, T. B. et al. Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies. Cell Host Microbe 16, 304–313 (2014). Mechanistic elucidation of the effects of genetic insertions and deletions in bnAb development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Henderson, R. et al. Structural basis for breadth development in the HIV-1 V3-glycan targeting DH270 antibody clonal lineage. Nat. Commun. 14, 2782 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Georgiev, I. S. et al. Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with Ig-framework regions substantially reverted to germline. J. Immunol. 192, 1100–1106 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. Sliepen, K. & Sanders, R. W. HIV-1 envelope glycoprotein immunogens to induce broadly neutralizing antibodies. Expert Rev. Vaccines 15, 349–365 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Kelsoe, G. & Haynes, B. F. Host controls of HIV broadly neutralizing antibody development. Immunol. Rev. 275, 79–88 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Julien, J. P. et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc. Natl Acad. Sci. USA 110, 4351–4356 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. McLellan, J. S. et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336–343 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cale, E. M. et al. Virus-like particles identify an HIV V1V2 apex-binding neutralizing antibody that lacks a protruding loop. Immunity 46, 777–791.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Rantalainen, K. et al. Co-evolution of HIV Envelope and apex-targeting neutralizing antibody lineage provides benchmarks for vaccine design. Cell Rep. 23, 3249–3261 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Willis, J. R. et al. Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. Immunity 55, 2149–2167.e9 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chen, J. et al. HIV-1 ENVELOPE. Effect of the cytoplasmic domain on antigenic characteristics of HIV-1 envelope glycoprotein. Science 349, 191–195 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Barnes, C. O. et al. Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope. Nat. Commun. 9, 1251 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Julien, J. P. et al. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog. 9, e1003342 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Mouquet, H. et al. Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc. Natl Acad. Sci. USA 109, E3268–E3277 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Zhou, T. et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811–817 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Zhou, T. et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732–737 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Huang, J. et al. Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 45, 1108–1121 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Gristick, H. B. et al. CD4 binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wild-type animals. Sci. Immunol. 8, eade6364 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. van Schooten, J. et al. Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein. Nat. Commun. 13, 4515 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Dam, K. A. et al. HIV-1 CD4-binding site germline antibody-Env structures inform vaccine design. Nat. Commun. 13, 6123 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Barnes, C. O. et al. A naturally arising broad and potent CD4-binding site antibody with low somatic mutation. Sci. Adv. 8, eabp8155 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Burton, D. R. et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266, 1024–1027 (1994).

    Article  CAS  PubMed  Google Scholar 

  164. Zhou, T. et al. A neutralizing antibody recognizing primarily N-linked glycan targets the silent face of the HIV Envelope. Immunity 48, 500–513.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Schoofs, T. et al. Broad and potent neutralizing antibodies recognize the silent face of the HIV envelope. Immunity 50, 1513–1529.e9 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Blattner, C. et al. Structural delineation of a quaternary, cleavage-dependent epitope at the gp41−gp120 interface on intact HIV-1 Env trimers. Immunity 40, 669–680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kong, R. et al. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. Science 352, 828–833 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. van Gils, M. J. et al. An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat. Microbiol. 2, 16199 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Huang, J. et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41–gp120 interface. Nature 515, 138–142 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Scharf, L. et al. Broadly neutralizing antibody 8ANC195 recognizes closed and open states of HIV-1 Env. Cell 162, 1379–1390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Klasse, P. J. Fusion peptide-directed antibodies: humoral armor against HIV-1 infection. Sci. Transl Med. 16, eadl2162 (2024).

    Article  CAS  PubMed  Google Scholar 

  172. Huang, J. et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406–412 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Yang, S. et al. Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack. Nat. Commun. 13, 6393 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Irimia, A., Sarkar, A., Stanfield, R. L. & Wilson, I. A. Crystallographic identification of lipid as an integral component of the epitope of HIV broadly neutralizing antibody 4E10. Immunity 44, 21–31 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Irimia, A. et al. Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design. PLoS Pathog. 13, e1006212 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Tan, K. et al. Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility. Nat. Commun. 14, 7218 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Rantalainen, K. et al. HIV-1 Envelope and MPER antibody structures in lipid assemblies. Cell Rep. 31, 107583 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Ray, R. et al. Affinity gaps among B cells in germinal centers drive the selection of MPER precursors. Nat. Immunol. 25, 1083–1096 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Schiffner, T. et al. Vaccination induces broadly neutralizing antibody precursors to HIV gp41. Nat. Immunol. 25, 1073–1082 (2024). The study represents a breakthrough in eliciting precursor-bnAb responses in animal models through immunization with MPER-epitope-mimicking scaffolds on nanoparticles.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Grunst, M. W. et al. Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. PLoS Pathog. 20, e1011819 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kong, R. et al. Antibody lineages with vaccine-induced antigen-binding hotspots develop broad HIV neutralization. Cell 178, 567–584.e19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Wang, S. et al. HIV-1 neutralizing antibodies elicited in humans by a prefusion-stabilized envelope trimer form a reproducible class targeting fusion peptide. Cell Rep. 42, 112755 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Xu, K. et al. Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1. Nat. Med. 24, 857–867 (2018). bnAbs were elicited by priming with FP conjugated to carrier and non-germline-adapted Env-trimer boosting: the structure of bnAb-Env complexes is solved.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Caniels, T. G. et al. Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions. Cell Rep. Med. 4, 101003 (2023). Immunization with germline-adapted Env trimer induces nAbs active against unmodified autologous and some heterologous virus isolates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Caniels, T. G. et al. Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site. Sci. Immunol. 9, eadk9550 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Cottrell, C. A. et al. Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice. Sci. Transl Med. 16, eadn0223 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Wang, X. et al. mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models. Sci. Immunol. 9, eadn0622 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kong, L. et al. Complete epitopes for vaccine design derived from a crystal structure of the broadly neutralizing antibodies PGT128 and 8ANC195 in complex with an HIV-1 Env trimer. Acta Crystallogr. D Biol. Crystallogr. 71, 2099–2108 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Jardine, J. G. et al. Minimally mutated HIV-1 broadly neutralizing antibodies to guide reductionist vaccine design. PLoS Pathog. 12, e1005815 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Yuan, M. et al. Conformational plasticity in the HIV-1 fusion peptide facilitates recognition by broadly neutralizing antibodies. Cell Host Microbe 25, 873–883.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Connolly, M. L. Analytical molecular surface calculation. J. Appl. Cryst. 16, 548–558 (1983).

    Article  CAS  Google Scholar 

  192. Guttman, M. et al. Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env. Nat. Commun. 6, 6144 (2015).

    Article  CAS  PubMed  Google Scholar 

  193. Mouquet, H. & Nussenzweig, M. C. Polyreactive antibodies in adaptive immune responses to viruses. Cell Mol. Life Sci. 69, 1435–1445 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. Bianchi, M. et al. Electron-microscopy-based epitope mapping defines specificities of polyclonal antibodies elicited during HIV-1 BG505 envelope trimer immunization. Immunity 49, 288–300.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Antanasijevic, A. et al. Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM. Nat. Commun. 12, 4817 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Williams, W. B. et al. Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies. Cell 184, 2955–2972.e25 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Sajadi, M. M. et al. Identification of near-pan-neutralizing antibodies against HIV-1 by deconvolution of plasma humoral responses. Cell 173, 1783–1795.e14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Yang, Y. R. et al. Autologous antibody responses to an HIV envelope glycan hole are not easily broadened in rabbits. J. Virol. 94, e01861-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Wagh, K. et al. Completeness of HIV-1 envelope glycan shield at transmission determines neutralization breadth. Cell Rep. 25, 893–908.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Williams, W. B. et al. Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans. Cell 187, 2919–2934.e20 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Steichen, J. M. et al. HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. Immunity 45, 483–496 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Hoot, S. et al. Recombinant HIV envelope proteins fail to engage germline versions of anti-CD4bs bNAbs. PLoS Pathog. 9, e1003106 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Jardine, J. G. et al. HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science 351, 1458–1463 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Medina-Ramirez, M. et al. Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. J. Exp. Med. 214, 2573–2590 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Scharf, L. et al. Structural basis for germline antibody recognition of HIV-1 immunogens. eLife 5, e13783 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Sliepen, K. et al. Binding of inferred germline precursors of broadly neutralizing HIV-1 antibodies to native-like envelope trimers. Virology 486, 116–120 (2015).

    Article  CAS  PubMed  Google Scholar 

  207. Stamatatos, L., Pancera, M. & McGuire, A. T. Germline-targeting immunogens. Immunol. Rev. 275, 203–216 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Xiao, X. et al. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens. Biochem. Biophys. Res. Commun. 390, 404–409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Mu, Z., Haynes, B. F. & Cain, D. W. Strategies for eliciting multiple lineages of broadly neutralizing antibodies to HIV by vaccination. Curr. Opin. Virol. 51, 172–178 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Lin, Y. R. et al. HIV-1 VRC01 germline-targeting immunogens select distinct epitope-specific B cell receptors. Immunity 53, 840–851.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. McGuire, A. T. et al. Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat. Commun. 7, 10618 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. McGuire, A. T. et al. Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies. J. Exp. Med. 210, 655–663 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Escolano, A. et al. Sequential immunization elicits broadly neutralizing anti-HIV-1 antibodies in Ig knockin mice. Cell 166, 1445–1458.e12 (2016). Pioneering immunization with germline-adapted Env results in bnAb-lineage responses in an animal model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Leggat, D. J. et al. Vaccination induces HIV broadly neutralizing antibody precursors in humans. Science 378, eadd6502 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sok, D. et al. Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice. Science 353, 1557–1560 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Cohen, J. Skin side effects stymie advance of HIV vaccine. Science 383, 1044 (2024).

    Article  CAS  PubMed  Google Scholar 

  217. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05471076 (2025).

  218. Bancroft, T. et al. Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes. J. Exp. Med. 216, 2331–2347 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Dosenovic, P. et al. Anti-idiotypic antibodies elicit anti-HIV-1-specific B cell responses. J. Exp. Med. 216, 2316–2330 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04224701 (2024).

  221. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05863585(2023).

  222. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05983874 (2024).

  223. Steichen, J. M. et al. A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses. Science 366, eaax4380 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Steichen, J. M. et al. Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates. Science 384, eadj8321 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Xie, Z. et al. mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies. Science 384, eadk0582 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT06033209 (2025).

  227. Saunders, K. O. et al. Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques. Cell 187, 79–94.e24 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are deeply grateful to M. Yuan (Figs. 1,2c,4 and 5b and Supplementary Fig. 1), R. Stanfield (Table 1) and G. Ozorowski (Fig. 3) for preparing figures and the table and performing the calculations they are based on. This work is supported by R01 AI036082 (to P.J.K. and J.P.M.), INV-063951 (to R.W.S.) and HIV Vaccine Research and Design (HIVRAD) grant AI110657 (to J.P.M., P.J.K., I.A.W., A.B.W. and R.W.S.).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    P. J. Klasse, Rogier W. Sanders & John P. Moore

  2. Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Rogier W. Sanders

  3. Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA

    Andrew B. Ward & Ian A. Wilson

Authors
  1. P. J. Klasse
    View author publications

    Search author on:PubMed Google Scholar

  2. Rogier W. Sanders
    View author publications

    Search author on:PubMed Google Scholar

  3. Andrew B. Ward
    View author publications

    Search author on:PubMed Google Scholar

  4. Ian A. Wilson
    View author publications

    Search author on:PubMed Google Scholar

  5. John P. Moore
    View author publications

    Search author on:PubMed Google Scholar

Contributions

P.J.K. researched data for the article. P.J.K. contributed substantially to discussion of the content. All authors wrote the article. P.J.K. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to P. J. Klasse.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Priyamvada Acharya and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klasse, P.J., Sanders, R.W., Ward, A.B. et al. The HIV-1 envelope glycoprotein: structure, function and interactions with neutralizing antibodies. Nat Rev Microbiol 23, 734–752 (2025). https://doi.org/10.1038/s41579-025-01206-6

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41579-025-01206-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing