Antibodies that neutralize diverse strains of HIV-1 develop in ~20% of HIV-1-infected people, and isolation and structural characterization of the antibodies is uncovering the way the envelope is acknowledged by them glycoprotein spike. with the trimeric Env spike. Nevertheless, these Env-directed replies consist mostly of non-neutralizing or strain-specific antibodies (analyzed in Pantophlet and Burton, 2006; Montefiori and Mascola, 2010). The type of the humoral immune system response is partly explained with the structural description from the SB-505124 HIV-1 envelope glycoprotein (Env) spike (Fig. 1), which reveals many systems of humoral evasion including sequence-variable loops, comprehensive glycosylation, and conformational masking of susceptible epitopes (Kwong et al., 2002; Starcich et al., 1986; Wyatt et al., 1998) analyzed in (Burton et al., 2005; Sattentau and Kong, 2012; Burton and Pantophlet, 2006; Verkoczy et al., 2011; Sodroski and Wyatt, 1998). These function in concert to inhibit the induction of neutralizing antibodies to conserved Env locations also to impede the identification from the viral spike by usually potentially KLRK1 defensive antibodies. Augmented by the entire genetic variability from the viral Env, these systems provide avenues for viral get away in the neutralizing antibody response also. Indeed, longitudinal research of HIV-1 SB-505124 infections show viral progression to outstrip the adaptive features from the antibody-mediated immune system response (Albert et al., 1990; Grey et al., 2007; Pilgrim et al., 1997; Richman et al., 2003; Rong et al., 2009; Sagar et al., 2006; Wei et al., 2003). Body 1 HIV-1 spike and its own identification by neutralizing antibodies This rather bleak watch from the humoral immune response to HIV-1 dominated the first 20 or so years of HIV-1 research, punctuated by the isolation and characterization of a few C less than ideal C cross-reactive neutralizing monoclonal antibodies (mAbs) such as b12, 2F5, 4E10 and 2G12 (Burton et al., 1994; Muster et al., 1994; Stiegler et al., 2001; Trkola et al., 1996) as well as by occasional reports of broadly neutralizing sera elicited in select HIV-1-infected donors (Binley et al., 2004; Mascola et al., 1994; Pilgrim et al., 1997). The development of panels of diverse HIV-1 isolates and of highly reproducible neutralization assays C capable of accurately quantifying the breadth and potency of HIV-1 neutralization from sera and mAbs (Binley et al., 2004; Blish et al., 2007; Li et al., 2005; Mascola et al., 2005; Seaman et al., 2010; Simek et al., 2009)C allowed cohorts of sera to be evaluated for their ability to neutralize HIV-1. Starting in ~2004, several groups of investigators began to report the identification of sera that could neutralize genetically diverse strains of HIV-1 (Binley et al., SB-505124 2008; Binley et al., 2004; Li et al., 2007; Piantadosi et al., 2009; Simek et al., 2009; Wu et al., 2006), with some sera neutralizing the majority of HIV-1 isolates tested (Binley et al., 2008; Doria-Rose et al., 2010; Li et al., 2007; Simek et al., 2009; Tomaras et al., 2011). Longitudinal studies exhibited that cross-reactive neutralizing antibodies generally arose after 2 to 4 years of HIV-1 contamination (Gray et al., 2011; Mikell et al., 2011; Moore et al., 2011) and analyses of such sera provided initial insights into the viral epitopes targeted by neutralization antibodies. A number of techniques, including affinity purification of serum antibodies and neutralization assays with epitope-specific mutant Env-pseudoviruses, were used to demonstrate that broadly reactive neutralizing sera contained antibodies to specific regions of the viral Env, including the CD4-binding site of gp120, glycan-containing regions on the surface of gp120, and the membrane-proximal external region of gp41 (MPER) (Binley et al., 2008; Gray et al., 2009a; Li et al., 2007; Li et al., 2009; Tomaras et al., 2011; Walker et al., 2010). Together, these studies provided proof-of-concept that this immune system can generate potent neutralizing antibodies against vulnerable regions of the HIV-1 Env. Difficulty with defining the specific antibodies responsible for the observed serum neutralization delayed further insight into the SB-505124 manner by which the humoral immune system effectively neutralized HIV-1. In the absence of neutralizing mAbs that recapitulated serum neutralization, it was unclear if serum neutralization resulted from polyclonal mixtures of antibodies that provided breadth by their cumulative or synergistic activity, or if serum neutralization resulted from a more limited subset of antibodies targeting conserved neutralization epitopes (Binley et al., 2008; Gray.