Guan Cell Biosci (2019) 9:2 https://doi.org/10.1186/s13578-018-0267-6 Cell & Bioscience
RESEARCH HIGHLIGHT Open Access The frst structure of HIV‑1 gp120 with CD4 and CCR5 receptors Yongjun Guan*
Abstract Shaik et al. recently published online the cryo-electron microscopy structure of HIV-1 gp120 in complex with CD4 and CCR5 receptors. This is the frst structure of the ternary HIV-1 gp120/CD4/CCR5 complex. This breakthrough of Env structure provides insights into HIV-1 fusion mechanism, CCR5 function, co-receptor switch, and, most importantly, the development of co-receptor-targeted therapeutic inhibitor and HIV-1 vaccine. It also shed lights on the immuno- genicity of gp120 by revealing the stably exposed conserved gp41-interactive region of gp120 in the complex. Keywords: gp120, CCR5, Cryo-EM, HIV-1, ADCC, Trogocytosis
Main text structural information on previous complexes of gp120 HIV-1 Env, a trimer of gp120–gp41 heterodimers, is the with CD4 and antibodies regarding the conformation of sole target of broadly neutralizing antibodies of which gp120, CCR5 and the interactions between gp120 and is believed to be a primary goal of HIV-1 vaccine devel- CCR5. Te interpretation of the structure, as the authors opment [1]. Env mediates membrane fusion after bind- addressed, provides insights into HIV fusion mechanism, ing CD4 receptor and a co-receptor CCR5/CXCR4. CCR5 function, co-receptor switch, and, most impor- Based on rich structural information of Env with CD4 tantly, the development of co-receptor-targeted thera- and with antibodies, it is well recognized that Env likes peutic inhibitor and HIV-1 vaccine. a conformational machine by transitioning between Te structure revealed details of the interactions conformations of prefusion-closed, CD4-bound, and co- between CCR5 and gp120. It showed that the V3 loop receptor-bound into a postfusion state to facilitate virus/ with its conserved tip inserts into the CCR5 binding target cell membrane fusion. Te initial CD4 receptor pocket, similar to that observed with the CCL5, and an binding displaces V1V2 loops from the Env’s apex, allows extended CCR5N terminus interacts with the gp120 co-receptor binding and opens up Env to enable gp41- bridging sheet. Most importantly, the structure of the mediated membrane fusion [2]. However, a structure of interactions between CCR5 and gp120 indicates that Env with co-receptor had been missing and leaved a gap maraviroc works by directly competing with the bind- in our knowledge of the interaction between Env and ing of gp120 to CCR5, which contrasts with the view in co-receptor.. the feld that maraviroc is an allosteric inhibitor. Based In a recent online article of Nature, Shaik et al. solved on the observation that the gp120 binding site on CCR5 the cryo-electron microscopy (cryo-EM) structure of mainly overlaps with maraviroc in the minor subpocket, a full-length monomeric gp120 in complex with a solu- the authors suggested a new design of more powerful ble CD4 ectodomain and an unmodifed human CCR5 therapeutic drugs by “adding additional groups to the tri- reconstituted into a lipid micelle [3]. Tis is the frst azole ring of maraviroc to enhance its competing potency structure of the ternary HIV-1 gp120/CD4/CCR5 com- with the V3 loop”. plex and a breakthrough in the feld. It adds a wealth of Te overall structural of gp120 in the complex with CD4 and CCR5 is very similar to the CD4-bound struc-
*Correspondence: [email protected] tural of Env [2]. Tis surprising observation led the Antibody BioPharm, Inc, 401 Professional Dr. Ste241, Gaithersburg, MD authors to imply that the co-receptor binding does not 20879, USA induce major conformational change of gp120 and the
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Guan Cell Biosci (2019) 9:2 Page 2 of 3
role of CCR5 binding is to stabilize the CD4-bound responses before a conclusive protective role of cluster A conformation of Env and to hold it closer to the cell antibody is evidenced. membrane. However, the structure might represent a In summary, the frst structure of HIV-1gp120 with postfusion state of monomeric gp120 bound to CD4 and CD4 and CCR5 revealed by Shaik et al. is a remarkable CCR5, therefore it may not reveal the changes induced progress in the feld. Te author made import insights by CCR5 binding in the complex of membrane anchored into HIV-1 fusion mechanism, function of CCR5, co- CD4, CCR5 and Env trimer structures. Te observed dif- receptor switch, as well as development of of novel inhib- ference that the N-terminus of the CCR5-bound gp120 itor and vaccine design. It also shed light on immune fips back onto the 7-stranded sheet of gp120 inner response against the conserved immunodominant cluster domain is mostly a late-entry structure as previously A region of gp120. revealed for the epitope structure of the cluster A C11- like antibody N12-i3 [4]. Abbreviations One remarkable highlight of the article is that the cryo-EM: cryo-electron microscopy; RFADCC: “rapid and fuorometric” authors were able to obtain a high-resolution cryo-EM antibody-dependent cellular cytotoxicity. structure of the gp120-CD4/CCR5 complex. Tis tech- Authors’ contributions nical success refects an important feature of the gp120- YG wrote the manuscript. The author read and approved the fnal manuscript. CD4/CCR5 complex that the complex can be stably extracted from target cell membrane. Tis feature shows Acknowledgements that the gp41-interactive region of gp120 in the late viral Not applicable. entry Env structure is well exposed on target cell mem- Competing interests brane and, therefore, is highly vulnerable to antibody YG is CEO of Antibody BioPharm Inc. immune response. Te gp41-interactive region of gp120 is mainly comprised conserved epitopes for the cluster Availability of data and materials Not applicable. A antibodies including A32-like, A32/C11 and C11-like antibodies [4]. Terefore, the article also shed an impor- Consent for publication tant light in immune response against Env in HIV infec- Not applicable. tion and Env vaccine. Ethics approval and consent to participate Antibodies specifc for the cluster A epitopes has been Not applicable. shown to be common and induced early in infection, and Funding may mediate the majority of ADCC activities detected in Not applicable. chronically infected individuals [5]. Tey were also impli- cated in protection for the clinical RV144 vaccine trial Publisher’s Note [6]. However, the role of cluster A antibodies is still not Springer Nature remains neutral with regard to jurisdictional claims in pub- defned. Te epitopes of cluster A antibodies are strictly lished maps and institutional afliations. receptor-binding dependent. Tey are not exposed on Received: 20 December 2018 Accepted: 26 December 2018 native trimer of HIV-1 viruses or productively infected cells [7]. Terefore, the antibodies may not have a direct impact on virus and productively infected cells. Further, a high throughput “rapid and fuorometric” antibody- References dependent cellular cytotoxicity (RFADCC) assay was 1. Sok D, Burton DR. Recent progress in broadly neutralizing antibodies to HIV. Nat Immunol. 2018;19:1179–88. commonly used to measure ADCC activity of cluster 2. Ward AB, Wilson IA. The HIV-1 envelope glycoprotein structure: nailing A antibodies [8]. Te RFADCC assay has been recently down a moving target. Immunol Rev. 2017;275:21–32. revealed to be actually measuring majority an antibody- 3. Shaik MM, Peng H, Lu J, Rits-Volloch S, Xu C, Liao M, Chen B. Structural basis of coreceptor recognition by HIV-1 envelope spike. Natre. 2018;12:1. dependent trogocytosis phenomenon instead of the 4. Tolbert WD, et al. Targeting the late stage of HIV-1 entry for antibody- assumed cell killing function of ADCC [9, 10], which has dependent cellular cytotoxicity: structural basis for Env epitopes in the imposed confusing results for the role of cluster A anti- C11 region. Structure. 2017;25:1719–31. 5. Veillette M, et al. The HIV-1 gp120 CD4-bound conformation is preferen- bodies. Cluster A antibody mediated Trogocytosis will tially targeted by antibody-dependent cellular cytotoxicity-mediating probably remove the well exposed antibody-gp120 com- antibodies in sera from HIV-1-infected individuals. J Virol. 2015;89:545–51. plexes from infected target cell surface by monocytes and 6. Bonsignori M, et al. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efcacy trial target multiple epitopes may result in escape of infected cells from the immune and preferentially use the VH1 gene family. J Virol. 2012;86:11521–32. surveillance. Terefore, it should be cautious for Env- 7. Lewis GK, et al. Epitope target structures of Fc-mediated efector function based vaccine development targeting cluster A antibody during HIV-1 acquisition. Curr Opin HIV AIDS. 2014;9:263–70. Guan Cell Biosci (2019) 9:2 Page 3 of 3
8. Gomez-Roman VR, et al. A simplifed method for the rapid fuorometric 10. Kramski M, et al. Role of monocytes in mediating HIV-specifc antibody- assessment of antibody-dependent cell-mediated cytotoxicity. J Immu- dependent cellular cytotoxicity. J Immunol Methods. 2012;384:51–61. nol Methods. 2006;308:53–67. 9. Alrubayyi A, et al. A fow cytometry based assay that simultaneously measures cytotoxicity and monocyte mediated antibody dependent efector activity. J Immunol Methods. 2018;462:74–82.
Ready to submit your research ? Choose BMC and benefit from:
• fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year
At BMC, research is always in progress.
Learn more biomedcentral.com/submissions