The rationally-designed immunogens developed in Projects 1 and 2 and produced in Core B will be tested in vivo in this Core for their ability to induce Abs in rabbits and/or non-human primates that are broadly reactive against HIV-1 isolates of different clades. The experiments will utilize an established DNA prime/protein boost protocol in which the DNA priming constructs will include Env genes, and the boosting constructs will consist of the V2-scaffold immunogen(s) and/or the QNE-scaffold immunogen(s). The work in Core C is divided into two specific aims:
Aim 1. To induce broad, potent, and long-lasting functional Ab responses in rabbits using rationally designed V2-scaffold immunogens as protein boosts subsequent to priming with Env genes. V2/V3 QNE-scaffold immunogens can only be tested in non-human primates because a) rabbits have not been shown to produce Abs carrying CDR H3 regions of the length needed for QNE-specific Abs, and b) it is not know if rabbits possess the immunoglobulin genes required to encode these Abs, whereas we have shown that SHIV-infected NHPs can produce QNE Abs. Thus, the V2/V3 QNE-scaffold immunogens will be tested in NHPs. In contrast, the V2-scaffold immunogens will first be tested in rabbits. To qualify for testing in NHPs, the V2-specific Ab responses achieved in rabbits will need to meet one or more of the following criteria: (a) Induction of Abs that neutralize the majority of Tier 1 pseudoviruses in the TZM.bl assay with titers better than 1:50;(b) Induction of Abs that neutralize >25% of Tier 2 pseudoviruses from at least two clades with titers better than 1:20 in at least one of the three neutralization assays used;(c) Induction of Abs that mediate additional anti-viral functions, and/or display neutralizing or other anti-viral activities against SHIVSFI62P3- Aim 2. To induce broad, potent, long-lasting and protective Ab responses in non-human primates using rationally designed V2- and/or V2/V3 QNEscaffold immunogens as protein boosts subsequent to priming with Env genes.
Experiments performed by this Animal Studies Core C are essential to the success of the entire HIVRAD, as animal testing will be performed in this Core to identify which immunogens and immunization protocols are best able to induce antibodies and protect against infection with HIV-1 in vivo.
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