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Title: Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Here, we report that antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. We define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. Lastly, we integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.
Authors:
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  1. Duke Univ. School of Medicine, Durham, NC (United States)
  2. National Inst. of Health (NIH), Bethesda, MD (United States)
  3. Columbia Univ., New York, NY (United States)
  4. Scripps Research Inst., La Jolla, CA (United States)
  5. National Inst. of Health (NIH), Bethesda, MD (United States); Vanderbilt Univ. Medical Center, Nashville, TN (United States)
  6. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
  7. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  8. Stanford School of Medicine, Palo Alto, CA (United States)
  9. Boston Univ., MA (United States)
  10. National Inst. of Health (NIH), Bethesda, MD (United States); Columbia Univ., New York, NY (United States)
Publication Date:
OSTI Identifier:
1259969
Report Number(s):
LA-UR--15-29619
Journal ID: ISSN 0092-8674; PII: S0092867416301246
Grant/Contract Number:
AC52-06NA25396; W-31-109-Eng-38; UM1 AI100645; UM1 AI100663; P01-AI104722
Type:
Accepted Manuscript
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 165; Journal Issue: 2; Journal ID: ISSN 0092-8674
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES