Diversion of HIV-1 vaccine–induced immunity by gp41-microbiota cross-reactive antibodies

Abstract

A HIV-1 DNA prime-recombinant Adenovirus Type 5 (rAd5) boost vaccine failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells was to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies (mAbs) were non-neutralizing, and frequently polyreactive with host and environmental antigens including intestinal microbiota (IM). Next generation sequencing of an IGHV repertoire prior to vaccination revealed an Env-IM cross-reactive Ab that was clonally-related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.

Structure-based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies

“…In a recent study (14) it was shown that vaccination with Env ectodomain (gp140) (HVTN clinical trials) also led to an antibody response dominated by gp41 reactive antibodies that were derived from pre-existing pools of intestinal microbiota cross- reactive B-cells (14). These results indicate that Env-based vaccines containing gp41 primarily induce non-neutralizing gp41 reactive antibodies (14,20,55). In the present study, we therefore omitted the gp41 subunit from the immunogen.…”

“…During acute infection, it was shown that the initial antibody responses are gp41 directed, non-neutralizing (53) and derived from polyreactive B cells that bind both Env and intestinal microbiota (54). In a recent study (14) it was shown that vaccination with Env ectodomain (gp140) (HVTN clinical trials) also led to an antibody response dominated by gp41 reactive antibodies that were derived from pre-existing pools of intestinal microbiota cross- reactive B-cells (14). These results indicate that Env-based vaccines containing gp41 primarily induce non-neutralizing gp41 reactive antibodies (14,20,55).…”

“…The bNAbs described to date target the CD4 binding site (CD4bs) on the gp120 subunit (NAbs b12, VRC01-03, NIH45-46, 3BNC117), quaternary epitopes in the V1V2 region on the gp120 trimer (PG9, PG16, PGT141-145, PGDM1400, and CAP256-VRC26. 25), glycan-dependent epitopes in the V3 loop (PGT series of NAbs), the membrane proximal external region of the gp41 subunit (NAbs 2F5, 4E10, and 10E8), and a cleavage-dependent epitope at the gp41-gp120 interface of the Env trimer (PGT151 and PGT152) (11)(12)(13)(14). The neutralizing epitopes on gp41 are Research, Government of India.…”

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

“…and Haynes B.F., unpublished) (Sanders and Moore, this volume). When gp41-containing Env immunogens are administered to humans the phenomenon described above in Figure 6 occurs whereby the vaccine-induced Env response to gp41 is a dominant microbiome cross-reactive non-neutralizing antibody response (91). Members of gp41 antibody lineages were present in pre-vaccination blood samples of vaccinees, demonstrating the existence of pre-existing gp41 cross-reactive clonal lineage members (91).…”

“…When gp41-containing Env immunogens are administered to humans the phenomenon described above in Figure 6 occurs whereby the vaccine-induced Env response to gp41 is a dominant microbiome cross-reactive non-neutralizing antibody response (91). Members of gp41 antibody lineages were present in pre-vaccination blood samples of vaccinees, demonstrating the existence of pre-existing gp41 cross-reactive clonal lineage members (91). Thus, the use of gp120 sequential Env immunogens to induce CD4bs CDR H3-binder type of bnAbs will test the hypothesis that gp120s that are antigenic for Env lineages can initiate and select antibody lineage members with progressive affinity maturation and neutralization capacity while bypassing gp41 diversion of gp120 antibody responses.…”