Abstract
SummaryBG505 SOSIP is a well-characterized near-native recombinant HIV Envelope (Env) trimer that holds promise as part of a sequential HIV immunogen regimen to induce broadly neutralizing antibodies (bnAbs). Rhesus macaques are considered the most appropriate pre-clinical animal model for monitoring antibody (Ab) responses. Accordingly, we report here the isolation of 45 BG505 autologous neutralizing antibodies (nAbs) with multiple specificities from SOSIP-immunized and BG505 SHIV-infected rhesus macaques. We associate the most potent neutralization with two epitopes: the C3/V5 and V1/V3 regions. We show that all of the nAbs bind in close proximity to known bnAb epitopes and might therefore sterically hinder elicitation of bnAbs. We also identify a “public clonotype” that targets the immunodominant C3/V5 nAb epitope, which suggests that common antibody rearrangements might help determine humoral responses to Env immunogens. The results highlight important considerations for vaccine design in anticipation of results of the BG505 SOSIP trimer in clinical trials.
Highlights
The elicitation of broadly neutralizing antibodies remains a key strategy in generating a protective HIV vaccine
High-Throughput Isolation of neutralizing antibodies (nAbs) to BG505 through B Cell Activation and Functional Screens To evaluate the immunogenicity of BG505 Env and the corresponding nAb specificities, we isolated monoclonal antibodies (mAbs) from BG505 SOSIP-immunized and SHIVBG505-infected macaques in the four groups listed above
In the high nAb titer group, vaccine-induced mAbs were isolated after the second or third immunization boost before simian-human immunodeficiency virus (SHIV) challenge (IMM) (Figure 1A)
Summary
The elicitation of broadly neutralizing antibodies (bnAbs) remains a key strategy in generating a protective HIV vaccine. Many groups in the field are exploring different approaches to the elicitation of bnAbs, including lineage-based design and germline targeting, to direct and guide the immune system to affinity mature specific antibody responses (Andrabi et al, 2018; Briney et al, 2016; Jardine et al, 2015, 2016; Sok et al, 2016a; Xu et al, 2018) Notwithstanding, these sequential immunization approaches will likely conclude with a native-like trimer to elicit antibodies that recognize the native Env trimer present on HIV (Burton, 2019). The best described and characterized among these is BG505 SOSIP.664 gp140 (BG505 SOSIP) (Sanders et al, 2013), which was the first trimer reported to reliably elicit potent autologous nAb responses in animal models by vaccination (Sanders et al, 2015)
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