The exception was the FP-targeting mAb Rh137.3, which showed binding to several Env trimers. C3/V5 nAb epitope, which suggests that common antibody rearrangements might help determine humoral responses to Env immunogens. The results spotlight important considerations for vaccine design in anticipation of results of the BG505 SOSIP trimer in clinical trials. == Graphical Abstract == == Highlights == SHIV-infected and SOSIP-immunized macaques elicit comparable neutralizing antibodies Four neutralizing epitope specificities are found in BG505 SOSIP-immunized macaques Antibodies to V1/V3 and C3/V5 are potently neutralizing and contribute to protection Public clonotype is usually recognized against immunodominant C3/V5 epitope ABBV-744 Zhao et al. statement the isolation and characterization of neutralizing antibodies from BG505 SHIV-infected and BG505 SOSIP-immunized macaques. Antibody responses between immunization and natural contamination are comparable and protective epitope specificities mapped. A common neutralizing antibody lineage (public clonotype) is recognized across several macaques targeting an immunodominant Cxcl12 epitope. == Introduction == The elicitation of broadly neutralizing antibodies (bnAbs) remains a key strategy in generating a protective HIV vaccine. These antibodies are capable of neutralizing a large diversity of HIV isolates by targeting relatively conserved epitopes around the HIV Env glycoprotein, which is the single target of nAbs and comprises a trimer of heterodimers, gp120 and gp41. Many groups in the field are exploring different approaches to the elicitation of bnAbs, including lineage-based design ABBV-744 and germline targeting, to direct and guideline 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 methods will likely conclude with a native-like trimer to elicit antibodies that identify the native Env trimer present on HIV (Burton, 2019). To this end, the field has generated a number of native-like trimer designs that have been characterized ABBV-744 and tested in different animal models (Bradley et al., 2016;Havenar-Daughton et al., 2016;Sanders and Moore, 2017;Sanders et al., 2015;de Taeye et al., 2016). The best explained and characterized among these is usually 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). Since it was first reported, BG505 SOSIP has been used to immunize a number of different animals, including rabbits, guinea pigs, cows, mice, humanized mice, and rhesus macaques (Feng et al., 2016;Hu et al., 2015;Pauthner et al., 2017;Sanders et al., 2015;Sok et al., 2017). Interestingly, the humoral responses vary considerably between the different animals. In mice and humanized mice, for example, neutralization was not detected, although strong binding titers were reported with the base of the trimer identified as immunodominant (Hu et al., 2015). Potent autologous nAbs were reliably reported in rabbits and guinea pigs, with the glycan hole centered on positions N241 and N289 as immunodominant in rabbits (Bianchi et al., 2018;Klasse et al., 2018;McCoy et al., 2016) and the C3/V4 epitope region as immunodominant in guinea pigs (Lei et al., 2019). In rhesus macaques, the nAb titers were lower than those observed in rabbits and guinea pigs and serum mapping studies recognized the C3/V5 epitope region as immunodominant (Cirelli et al., 2019;Klasse et al., 2018;Sanders et al., 2015). Finally, in cows, immunization with the BG505 SOSIP alone resulted in quick, broad, and potent nAb responses, which were directed to the CD4 binding site (Sok et al., 2017). These different immune responses highlight the important role of antibody repertoires in shaping immunodominant responses to the same trimer immunogen. Importantly, monoclonal antibodies (mAbs) have been isolated and characterized for all of the animals yielding nAb responses but only few for rhesus macaques (Cottrell et al., 2020). MAbs provide a more detailed view of the epitopes targeted on HIV Env, and comparison of their sequences might reveal common signatures that contribute to immunogenicity. Additionally, first-in-human phase I trials have initiated for BG505 SOSIP at three clinical trial sites, two in the United States, and one in Kenya. The availability of mAbs from immunized rhesus macaques might provide early insight to what responses are predicted in humans given the close similarities between the macaque and human immunoglobulin (Ig) loci (Sundling et al., 2012). Additionally, once data from your human trial are available, a comparison of serum immune responses and mAbs will determine which animal model is the most predictive of immune responses observed in humans and therefore the one most appropriate for further study. In this study, we statement the isolation and characterization of monoclonal nAbs from BG505 SOSIP-immunized Indian rhesus macaques. This work follows immunization of rhesus macaques with BG505 SOSIP that generated varying serum levels of autologous nAbs (Pauthner et al., 2017). Six animals with high serum nAb titers,.