Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity.

TitleAnti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity.
Publication TypeJournal Article
Year of Publication2018
AuthorsDosenovic P, Kara EE, Pettersson A-K, McGuire AT, Gray M, Hartweger H, Thientosapol ES, Stamatatos L, Nussenzweig MC
JournalProc Natl Acad Sci U S A
Volume115
Issue18
Pagination4743-4748
Date Published05/01/2018
ISSN1091-6490
Abstract

The discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody-based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination and instead would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin (Ig) knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain superphysiologic numbers of bNAb precursor-expressing B cells, and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center (GC) B cell recruitment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the GC when there are as few as 10 such cells per mouse. However, at low precursor frequencies, the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to GCs is variable and dependent on recirculation.

DOI10.1073/pnas.1803457115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29666227
PubMed Central IDPMC5939114
Grant ListR01 AI037526 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
R01 AI081625 / AI / NIAID NIH HHS / United States
R01 AI104384 / AI / NIAID NIH HHS / United States
R37 AI037526 / AI / NIAID NIH HHS / United States
K99 AI127243 / AI / NIAID NIH HHS / United States
CHAVI-ID: 
1
Cover Picture: 
Sal-List: