2, C and D) in Ribi (Rees et al
2, C and D) in Ribi (Rees et al., 1999; Moon et al., 2007). anti-idiotypic antibody, iv8, that selects for naive human B cells expressing immunoglobulin light chains with 5Camino acid complementarity determining region 3s, a key feature of anti-CD4 binding site (CD4bs)Cspecific VRC01-class antibodies. In mice, iv8 induced target cells to expand and mature in the context of a polyclonal immune system and produced serologic responses targeting the CD4bs on Env. In summary, the results demonstrate that an anti-idiotypic antibody can specifically recognize and expand rare B cells that express VRC01-class antibodies against HIV-1. Graphical Abstract Open in a separate window Introduction Despite nearly four decades of investigation, there is still no vaccine against HIV-1. However, broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the HIV-1 envelope (Env) are protective against infection by diverse viral strains in animal models (Burton and Hangartner, 2016; Haynes et al., 2016; Escolano et al., 2017; Kwong and Mascola, 2018). Thus, it is widely believed that a vaccine that elicits such antibodies would also be protective in humans. VRC01-class antibodies are among the broadest and most potent bNAbs isolated to date. These antibodies share the same Ig heavy chain (IgH) V gene, VH1-2*02, which encodes a CDRH2 (complementary determining region 2, heavy chain) region that makes critical contacts with the CD4 binding site (CD4bs) on Env (Zhou et al., 2010, 2013, 2015; Diskin et al., 2011; Huang et al., 2016; Sajadi et al., 2018). In addition, these antibodies express Ig light chains (IgLs) with 5-aa-long CDRL3s (complementary determining region 3, light chain), a rare feature of human IgLs that is nonetheless required to accommodate the CDRH2-restricted mode of binding (West et al., 2012; Zhou et al., 2013). An important impediment to vaccine development against HIV-1 is that immunization with soluble or multimerized recombinant Env proteins elicits antibodies that are type specific but show little or no neutralization breadth against heterologous viral variants (McCoy and Weiss, 2013; Sliepen and Sanders, 2016; Karlsson Hedestam et al., 2017; van Schooten and van Gils, 2018). This problem is not specific to HIV-1 but is also shared to a lesser extent with other variable pathogens such as influenza, Zika, and dengue virus (Brien et al., 2010; Fajardo et al., 2016; Wu and Wilson, 2017). Several different strategies have been devised to try to resolve this issue by focusing humoral responses on conserved epitopes. Examples include the development of scaffolds that carry the conserved epitopes (Ofek et al., 2010; Azoitei et al., 2011; Correia et al., 2014; Zhou et al., 2014), the use of short linear peptides that encompass target epitopes (Wang et al., 2010; Alam et al., 2017; Xu et al., 2018), shielding WYE-354 or deletion of off-target antigenic surfaces that are immunodominant (Barnett et al., 2001; Cherpelis et al., 2001; M?rner et al., 2009; Eggink et al., 2014; Yassine et al., 2015; Duan et al., 2018), and sequential immunization with different antigens that share the target epitope (M?rner et al., 2009; Guenaga et al., 2011). An additional problem is that with few exceptions, the unmutated common ancestors of HIV-1 bNAbs fail to bind Env immunogens (Xiao et al., 2009; Huber et al., 2010; Zhou et al., 2010; Bonsignori et WYE-354 al., 2011, 2016; Ma et al., 2011; Scheid et al., 2011; Mouquet et al., 2012; Hoot et al., 2013; Jardine et al., 2013; Liao et al., 2013; McGuire et KDM5C antibody al., WYE-354 2013, 2014b; Sok et al., 2013; Doria-Rose et al., 2014; Andrabi et al., 2015; Bhiman et al., 2015; Gorman et al., 2016; Stamatatos et al., 2017). To overcome this problem, Env proteins were.