QA013.2 bnAb polyreactivity as measured by ELISA. HIV subtypes (Burton and Hangartner, 2016;Doria-Rose, 2010). The potency and protective effectiveness of these bnAbs has been demonstrated in passive immunization tests (Pegu et al., 2017), however thus far, no vaccine design has been capable of eliciting potent HIV bnAbs. In part, this may be because HIV-specific bnAbs typically take years to develop in adults, requiring exposure of the immune system to significant, growing viral diversity, and have unusual features including prolonged ITIC-4F complementarity determining areas (CDRs), common somatic hypermutation (SHM), and polyreactivity (Mascola ITIC-4F and Haynes, 2013). Developing a vaccine DHCR24 that stimulates the production of neutralizing antibodies with such rare features may require a series of immunogens that every engage key intermediate members of the antibodys lineage, leading to eventual bnAb emergence (Andrabi et al., 2018;Kwong and Mascola, 2018). Using deep sequencing and phylogenetic approaches to define maturation pathways of bnAbs using their naive predecessors in the establishing of natural illness provides insight that can guide the design of tailored vaccine immunogens aimed at recapitulating the development and development of HIV-specific bnAbs (Briney et al., 2016;Doria-Rose and Joyce, 2015). Such antibody lineage reconstruction has been performed for a handful of HIV bnAbs, with particular focus on core bnAb epitopes including the CD4-binding site, the variable loop 1/2 (V1/V2) apex, and the conserved glycan supersite in V3 of HIV Envelope (Env) (Bonsignori et al., 2017a;Doria-Rose et al., 2016;Garces et al., 2015;Kong et al., 2016;Krebs et al., 2019;IAVI Protocol C Investigators et al., 2017;IAVI Protocol C Investigators & The IAVI African HIV Study Network et al., ITIC-4F 2016;Doria-Rose et al., 2014;Simonich et al., 2019;IAVI Protocol C Investigators et al., 2019;Wu et al., 2011). The glycan supersite in the V3 loop of Env is an advantageous target for vaccine immunogens because bnAbs realizing this site are not germline restricted and often require less SHM than several other bnAb classes (IAVI Protocol C Investigators & The IAVI African HIV Study Network et al., 2016;Simonich et al., 2019). While V3/glycan-specific bnAbs have a shared requirement of the core glycan at site N332, they are also capable of realizing heterogeneous glycan moieties with overlapping epitopes and they achieve this acknowledgement using a variety of binding perspectives and methods (Barnes et al., 2018;Bonsignori et al., 2017a;Doores et al., 2015;Freund ITIC-4F et al., 2017;Julien et al., 2013;Mouquet et al., 2012;Pejchal et al., 2011;Sok et al., 2016;Trkola et al., 1996, p. 12;Protocol G Principal Investigators et al., 2011). The majority of HIV isolates are able to escape V3/glycan-specific bnAb acknowledgement and neutralization by shifting the sites of glycosylation on the surface of Env (Dingens et al., 2019), but combination immunotherapy with bnAbs that target distinct epitopes offers demonstrated the ability to thwart viral escape, without the emergence of resistance mutations (Bar-On et al., 2018;Klein et al., 2012;Mendoza et al., 2018). These findings support the use of genetically varied immunogens during vaccination to generate a polyclonal neutralizing antibody response that focuses on unique epitopes, as is definitely observed following natural HIV superinfection (Cortez et al., 2015;Doria-Rose and Joyce, 2015;Williams et al., 2018). HIV superinfection (SI) represents a unique setting to study the development of bnAbs, as antigenic activation with two genetically unique computer virus strains may lead to.