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

Abstract

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.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…Some bnAb types such as gp41 MPER bnAbs (2F5, 4E10, DH511 and 10E8) must have hydrophobic CDR H3s for binding to the virion membrane, and bnAb precursors with these characteristics are either deleted in bone marrow or became anergic in the periphery (98, 105–109). Other bnAb types such as CD4bs antibodies are either not deleted in bone marrow or less so than gp41 antibodies, but rather antibody poly-reactivity or auto-reactivity is acquired later in bnAb B cell lineage maturation (17).…”

“…We have now reconstructed bnAb lineages from a number of HIV-1 infected individuals that made either gp41 membrane proximal lineage bnAbs (89, 98) (Williams L., Haynes B.F. et al unpublished), CD4bs bnAbs (16–18), V1V2-glycan bnAbs (15) or V3-glycan bnAbs (Bonsignori M. et al, submitted). Here we discuss the use of antibody and virus co-evolution mapping data to design a first generation of immunogens for induction of two types of CD4bs bnAb B cell lineages, CDR H3-binder and V H 1-46 CD4 mimicking CD4bs bnAbs, and for V3-glycan bnAbs (see also Korber, Hraber, Wagh and Hahn, this volume).…”

What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination?

“…These divergent fates are controlled by counterpoised transcriptional regulators, Blimp-1 and Bach2, but how each fate is established remains unclear (Shinnakasu et al 2016). HIV-1 Env vaccine antigens induce specific and high-affinity antibody and, especially when serial vaccine strategies are used (Haynes et al 2012), are capable of driving high frequencies of V(D)J mutation (Zhang et al 2016). Why then do HIV-1 Env vaccines not routinely induce bnAb responses?…”

“…Evidence for immune control of bnAbs in primates comes from a recent study in rhesus macaques whereby immunization with a vaccine immunogen that wasavidly boundbythe germ-line, unmutated precursor of the 2F5 bnAb-induced 2F5-like antibodies that were rapidly lost on continued immunization (Zhang et al 2016). The ability of gp41 membrane proximal bnAbs, including 2F5, to neutralize depends on acquisition of a hydrophobic HCDR3 that mediates a fast association rate for virion binding (Fig.…”

“…The ability of gp41 membrane proximal bnAbs, including 2F5, to neutralize depends on acquisition of a hydrophobic HCDR3 that mediates a fast association rate for virion binding (Fig. 1A) (Zhang et al 2016). In this study, immunization elicited alternative forms of gp41-reactive antibodies that bound at/near the 2F5 epitope and accumulated V(D)J mutation frequencies of >10%, but nonetheless exhibited slower association rates than bnAbs (Fig.…”