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Edited by David Baker, University of Washington, Seattle, WA, and approved February 26, 2016 (received for review September 16, 2015)
Significance
When HIV neutralizing antibody (Ab) responses occur, they are often mediated by Abs with exceptional levels of somatic mutation. An exception are HIV neutralizing Abs that feature long heavy-chain complementarity-determining region 3 (HCDR3) regions, such as the Ab PG9. Relative to many other HIV broadly neutralizing Abs (bnAbs), PG9 has fewer somatic mutations than most potent bnAbs. Here we used deep-sequencing and computational methods to identify a panel of HCDR3 sequences in HIV-naïve donors that mediated binding and neutralization of HIV by mimicking the bnAb PG9 long HCDR3 region when expressed in the context of the rest of the PG9 antibody sequence. Thus, it may be possible for structure-based vaccine design efforts to engage long HCDR3s available in the HIV-naïve Ab repertoire and elicit a neutralizing response.
Abstract
Development of broadly neutralizing antibodies (bnAbs) against HIV-1 usually requires prolonged infection and induction of Abs with unusual features, such as long heavy-chain complementarity-determining region 3 (HCDR3) loops. Here we sought to determine whether the repertoires of HIV-1–naïve individuals contain Abs with long HCDR3 loops that could mediate HIV-1 neutralization. We interrogated at massive scale the structural properties of long Ab HCDR3 loops in HIV-1–naïve donors, searching for structured HCDR3s similar to those of the HIV-1 bnAb PG9. We determined the nucleotide sequences encoding 2.3 × 107 unique HCDR3 amino acid regions from 70 different HIV-1–naïve donors. Of the 26,917 HCDR3 loops with 30-amino acid length identified, we tested 30 for further study that were predicted to have PG9-like structure when chimerized onto PG9. Three of these 30 PG9 chimeras bound to the HIV-1 gp120 monomer, and two were neutralizing. In addition, we found 14 naturally occurring HCDR3 sequences that acquired the ability to bind to the HIV-1 gp120 monomer when adding 2- to 7-amino acid mutations via computational design. Of those 14 designed Abs, 8 neutralized HIV-1, with IC50 values ranging from 0.7 to 98 µg/mL. These data suggest that the repertoire of HIV-1–naïve individuals contains rare B cells that encode HCDR3 loops that bind or neutralize HIV-1 when presented on a PG9 background with relatively few or no additional mutations. Long HCDR3 sequences are present in the HIV-naïve B-cell repertoire, suggesting that this class of bnAbs is a favorable target for rationally designed preventative vaccine efforts.
Footnotes
↵1Present address: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
↵2Present address: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
- ↵3To whom correspondence may be addressed. Email: jens.meiler{at}vanderbilt.edu or james.crowe{at}vanderbilt.edu.
Author contributions: J.R.W., J.A.F., B.B., J.M., and J.E.C. designed research; J.R.W., J.A.F., B.B., G.S., V.S., H.K., C.C.L., and D.C.M. performed research; J.A.F. contributed new reagents/analytic tools; J.R.W., J.A.F., C.C.L., D.C.M., and J.M. analyzed data; and J.R.W., J.M., and J.E.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1518405113/-/DCSupplemental.
http://www.pnas.org/preview_site/misc/userlicense.xhtml
Long antibody HCDR3s from HIV-naïve donors and HIV
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