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Initiation of immune tolerance–controlled HIV gp41 neutralizing B cell lineages

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Science Translational Medicine  27 Apr 2016:
Vol. 8, Issue 336, pp. 336ra62
DOI: 10.1126/scitranslmed.aaf0618

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An immune block to HIV vaccines

Because HIV is a rapidly mutating virus, a successful vaccine will need to elicit an immune response against a variety of HIV strains—broadly neutralizing antibodies (bnAbs). However, despite multiple promising targets, bnAb generation after HIV vaccination has remained elusive. Now, Zhang et al. report that bnAbs to one such target, gp41, are controlled by immune tolerance. In mouse and macaque, precursors to these antibodies are either deleted or do not attain sufficient affinity to neutralize virus. Therefore, a successful vaccine for HIV will need to overcome immune tolerance mechanisms.


Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls.

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