It is now well-established that 10-20% of those infected with HIV-1 will generate cross-neutralizing antibody responses, similar to those we hope to elicit by immunization. The target of anti-HIV NAbs is the viral envelope glycoprotein (Env) and over the past two decades, different forms of HIV Env-based immunogens have been evaluated for their ability to elicit bNAbs. Unfortunately, although such constructs are immunogenic in diverse animal species, as well as humans, they do not elicit the desired broad anti-HIV-1 neutralizing antibody responses, despite the presence on these immunogens of the epitopes targeted by these broadly neutralizing antibodies. Currently, it is unknown whether Env-based immunogens stimulate B cells that express B Cell Receptors (BCRs) that target these epitopes, to proliferate and to differentiate. Here we propose to take advantage of key recent findings, and of new reagents, to not only optimize the design of soluble Env-based immunogens to express epitopes that are targeted by known bNAbs, but also to monitor, in depth, the evolution of the human BCR during Env-immunization. We will thus assess whether our immunogens engage the desired germline BCRs in vivo; whether this engagement leads to the initiation of the maturation process of the desired BCR; how and whether repeated immunization affects the rate of somatic hypermutations of the desired BCR; and how far along the path of BCR-maturation we can drive this process by utilizing the recombinant Env constructs we have in our disposal.
Our proposed studies are highly significant to the eventual development of an effective vaccine against HIV-1, because they aim at eliciting broad and potent neutralizing antibody responses against this pathogen.
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