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Title: Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

Here, the extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160) 3, cleaved to (gp120/gp41) 3] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length, membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160) 3, retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization bymore » all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.« less
Authors:
 [1] ;  [2] ;  [1] ;  [2] ;  [3] ;  [2] ;  [1] ;  [4] ; ORCiD logo [5] ; ORCiD logo [5] ;  [5] ;  [3] ;  [1] ;  [6] ;  [1]
  1. Boston Children's Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  2. GlaxoSmithKline Vaccines, Rockville, MD (United States)
  3. Beth Israel Deaconess Medical Center, Boston, MA (United States)
  4. Codex BioSolutions, Inc., Gaithersburg, MD (United States)
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. GlaxoSmithKline Vaccines, Rockville, MD (United States); Valera LLC, Cambridge, MA (United States)
Publication Date:
Report Number(s):
LA-UR-16-29058
Journal ID: ISSN 0027-8424
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 17; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
Universities/Institutions; USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science; HIV-1 gp160; neutralizing antibodies; vaccine design
OSTI Identifier:
1374321