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

WB Williams, HX Liao, MA Moody, TB Kepler, SM Alam… - Science, 2015 - science.org
WB Williams, HX Liao, MA Moody, TB Kepler, SM Alam, F Gao, K Wiehe, AM Trama, K Jones
Science, 2015science.org
INTRODUCTION Inducing protective antibodies is a key goal in HIV-1 vaccine development.
In acute HIV-1 infection, the dominant initial plasma antibody response is to the gp41
subunit of the envelope (Env) glycoprotein of the virus. These antibodies derive from
polyreactive B cells that cross-react with Env and intestinal microbiota (IM) and are unable to
neutralize HIV-1. However, whether a similar gp41-IM cross-reactive antibody response
would occur in the setting of HIV-1 Env vaccination is unknown. RATIONALE We studied …
INTRODUCTION
Inducing protective antibodies is a key goal in HIV-1 vaccine development. In acute HIV-1 infection, the dominant initial plasma antibody response is to the gp41 subunit of the envelope (Env) glycoprotein of the virus. These antibodies derive from polyreactive B cells that cross-react with Env and intestinal microbiota (IM) and are unable to neutralize HIV-1. However, whether a similar gp41-IM cross-reactive antibody response would occur in the setting of HIV-1 Env vaccination is unknown.
RATIONALE
We studied antibody responses in individuals who received a DNA prime vaccine, with a recombinant adenovirus serotype 5 (rAd5) boost (DNA prime–rAd5 boost), a vaccine that included HIV-1 gag, pol, and nef genes, as well as a trivalent mixture of clade A, B, and C env gp140 genes containing both gp120 and gp41 components. This vaccine showed no efficacy. Thus, study of these vaccinees provided an opportunity to determine whether the Env-reactive antibody response in the setting of Env vaccination was dominated by gp41-reactive antibodies derived from Env-IM cross-reactive B cells.
RESULTS
We found that vaccine-induced antibodies to HIV-1 Env dominantly focused on gp41 compared with gp120 by both serologic analysis and by vaccine-Env memory B cells sorted by flow cytometry (see the figure). Remarkably, the majority of HIV-1 Env-reactive memory B cells induced by the vaccine produced gp41-reactive antibodies, and the majority of gp41-targeted antibodies used restricted immunoglobulin heavy chain variable genes. Functionally, none of the gp41-reactive antibodies could neutralize HIV, and the majority could not mediate antibody-dependent cellular cytotoxicity. Most of the vaccine-induced gp41-reactive antibodies cross-reacted with host and IM antigens. Two of the candidate gp41-intestinal cross-reactive antigens were bacterial RNA polymerase and pyruvate-flavodoxin oxidoreductase, which shared sequence similarities with the heptad repeat 1 region of HIV gp41. Next-generation sequencing of vaccinee B cells demonstrated a prevaccination antibody that was reactive to both IM and the vaccine–Env gp140, which demonstrated the presence of a preexisting pool of gp41-IM cross-reactive B cells from which the vaccine gp41-reactive antibody response was derived.
CONCLUSION
In this study, we found that the DNA prime–rAd5 boost HIV-1 vaccine induced a gp41-reactive antibody response that was mainly non-neutralizing and derived from an IM-gp41 cross-reactive B cell pool. These findings have important implications for HIV-1 vaccine design. Because IM antigens shape the B cell repertoire from birth, our data raise the hypothesis that neonatal immunization with HIV-1 envelope may be able to imprint the B cell repertoire to respond to envelope antigenic sites that may otherwise be subdominant or disfavored, such as Env broadly neutralizing antibody epitopes. Our data also suggest that deleting or modifying amino acids in the gp41 heptad repeat 1 region of Env-containing vaccine immunogens may avoid IM-gp41 cross-reactivity. Thus, an obstacle that may need to be overcome for development of a successful HIV vaccine is diversion of potentially protective HIV-1 antibody responses by preexisting envelope-IM cross-reactive pools of B cells.
AAAS