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Title: An MPER antibody neutralizes HIV-1 using germline features shared among donors

Journal Article · · Nature Communications
 [1];  [2];  [2];  [3];  [2];  [2]; ORCiD logo [4];  [2]; ORCiD logo [2]; ORCiD logo [2];  [3]; ORCiD logo [5];  [6]; ORCiD logo [2];  [2]; ORCiD logo [2];  [2]
  1. The Scripps Research Inst., La Jolla, CA (United States); DOE/OSTI
  2. The Scripps Research Inst., La Jolla, CA (United States)
  3. The Scripps Research Inst., La Jolla, CA (United States); International AIDS Vaccine Initiative, New York, NY (United States)
  4. Univ. of California, San Diego, CA (United States)
  5. The Scripps Research Inst., La Jolla, CA (United States); MIT and Harvard, Cambridge, MA (United States). Ragon Institute of Massachusetts General Hospital
  6. Univ. of California, San Diego, CA (United States); Karolinska Institutet, Stockholm (Sweden). Department of Microbiology, Tumor and Cell Biology

The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. Here we describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. A recombinant sublineage variant pan-neutralizes a 130-isolate panel at 1.4 μg/ml (IC50). Notably, a germline revertant with mature CDR3s neutralizes 12% of viruses and still binds MPER after DJ reversion. Crystal structures of lipid-bound PGZL1 variants and cryo-EM reconstruction of an Env-PGZL1 complex reveal how these antibodies recognize MPER and viral membrane. Discovery of common genetic and structural elements among MPER antibodies from different patients suggests that such antibodies could be elicited using carefully designed immunogens.

Research Organization:
SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); HIV Vaccine Research and Design (HIVRAD); James B. Pendleton Charitable Trust; United States Agency for International Development (USAID), Ministry of Foreign Affairs of the Netherlands; Bill & Melinda Gates Foundation; National Institute of General Medical Sciences (NIGMS)
Contributing Organization:
IAVI Protocol G Investigators
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1624211
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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