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Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/JVI.01280-15· OSTI ID:1213730
 [1];  [2];  [1];  [3];  [1];  [1];  [1];  [2];  [4];  [1];  [1];  [2];  [1]
  1. Veterans Affairs New York Harbor Healthcare System, New York, NY (United States); NYU School of Medicine, New York, NY (United States)
  2. NYU School of Medicine, NY (United States)
  3. Veterans Affairs New York Harbor Healthcare System, New York, NY (United States); NYU School of Medicine, New York, NY (United States); Univ. de Strasbourg (France)
  4. Harvard Medical School, Boston, MA (United States)
+ Show Author Affiliations
The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown (307IHIGPGRAFYT319), dominated by interactions with HisP308, ProP313, and ArgP315. The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, although 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. Lastly, this feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); NIH; National Cancer Inst.; National Inst. of General Medical Sciences
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1213730
Journal Information:
Journal of Virology, Journal Name: Journal of Virology Journal Issue: 17 Vol. 89; ISSN 0022-538X
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Difficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations journal July 2019

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