![]() Antibody-virus co-evolution studies from the time of HIV-1 transmission through bnAb development have shown that bnAbs arise after extensive Env diversification and when bnAbs develop, they are subdominant with respect to other Env lineages 6– 8.īnAb knock-in (KI) mice have proved useful for bnAb development and regulation studies. However, Env-immunogens including stabilized trimers have thus far been ineffective for inducing broadly neutralizing antibodies (bnAbs) in humans or wild-type animals 2– 5. The HIV-1 envelope (Env) is the target of neutralizing antibodies (nAb) 1. ![]() Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env + (non-edited) precursor B cells. In naive CD4bs, unmutated common ancestor knock-in mice Env +B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env − upon receptor editing. ![]() Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. ![]() Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. ![]()
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