Abstract
Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs arehighly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design.
Highlights
A fraction of HIV-1-infected individuals mount a broadly neutralizing serologic response (Doria-Rose et al, 2010; Simek et al, 2009) 2–3 years after infection (Mikell et al, 2011)
In contrast to most other antibodies, including anti-HIV-1 antibodies with limited neutralization activity, we found that framework regions (FWRs) mutations, including noncontact residues, are essential for the neutralizing activity of most potent bNAbs
We propose that the requirement to alter the FWR, without destroying its essential structural elements, accounts for the high mutation load found in broadly neutralizing anti-HIV-1 antibodies and possibly for the difficulty and prolonged latency with which such antibodies develop
Summary
A fraction of HIV-1-infected individuals mount a broadly neutralizing serologic response (Doria-Rose et al, 2010; Simek et al, 2009) 2–3 years after infection (Mikell et al, 2011). Antibodies generated by these individuals are of great interest for vaccine design because they can protect macaques from infection (Mascola et al, 2000; Moldt et al, 2012; Shibata et al, 1999). Combinations of broadly neutralizing antibodies can control an established HIV-1 infection in humanized mice (Klein et al, 2012b)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
