Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes

Bancroft, Tara; DeBuysscher, Blair L.; Weidle, Connor; Schwartz, Allison; Wall, Abigail; Gray, Matthew D.; Feng, Junli; Steach, Holly R.; Fitzpatrick, Kristin S.; Gewe, Mesfin M.; Skog, Patrick D.; Doyle-Cooper, Colleen; Ota, Takayuki; Strong, Roland K.; Nemazee, David; Pancera, Marie; Stamatatos, Leonidas; McGuire, Andrew T.; Taylor, Justin J.

The existence of deletion and anergy in mice suggested that immunization strategies able to overcome tolerance may be required to stimulate the production of b12-like bNAbs in humans. The need to overcome tolerance is not unique to iglb12 knock-in mice, since deletion and anergy have also been detected in mice expressing the inferred germline forms of the HIV-1 bNAbs 4E10 and 3BNC60 (McGuire et al., 2016; Zhang et al., 2016) . Autoreactivity is not a unique feature of some HIV-specific lineages and has been detected in assessments of influenza bNAbs (Andrews et al., 2015; Bajic et al., 2019) . Notably, it remains possible that the tolerance exhibited in transgenic mice expressing the iglb12 heavy chain is an artifact of the inability to accurately infer the true unmutated heavy chain CDRH3 from the mature b12 antibody. For example, the CDRH3 in this sequence contains two N regions that cannot be inferred and are instead carried over from the mature sequence. It is possible that the true germline heavy chain CDRH3 had different sequences in these locations that would not have resulted in deletion and anergy.