HIV-1 is characterized by an extraordinary genetic diversity, reflected by the presence of several clades (subtypes), a fact that represents a significant impediment to vaccine development. Env is the most variable HIV-1 gene, with up to 35% sequence diversity among clades, 20% diversity within clades, and 10% diversity in a single infected individual [15, 16, 17] . Several conserved epitopes have been defined by a small panel of neutralizing mAbs isolated using different experimental approaches. One epitope that appears to be relatively conserved and overlaps with the CD4 binding site (CD4bs) on the surface Env glycoprotein gp120 is recognized by mAb b12, which is the most potent and broadly-reactive mAb of such specificity [18, 19, 20] . This site was recently shown to be a significant target of neutralizing antibodies present in the sera of selected patients [21, 22] . However, b12 was derived from a phage library in which heavy and light chains have been randomly reassorted, thus its relevance to naturally-occurring B cell responses in HIV-1 infection is unclear. A second epitope in a carbohydraterich region on the outer domain of gp120 is composed of glycans recognized by mAb 2G12, which shows an unusual interlocked VH domain-swapped dimer generating an extended and monovalent binding surface [23, 24, 25, 26] . The 2G12 epitope is not present in the majority of clade C isolates [27] , but, of more concern, no 2G12-like activity has been detected in the sera of HIV-1 infected individuals [21, 22] , suggesting that this type of neutralizing antibody may not be generally amenable to elicitation by B cells. A third target of the broadly-neutralizing mAb 4E10, and relatively broad mAbs 2F5 and Z13, is located on the membrane-proximal external region (MPER) of the transmembrane glycoprotein gp41 [28, 29, 30, 31] . As with 2G12, MPERspecific neutralizing antibodies are infrequently encountered in the sera of HIV-1-infected individuals [21, 32, 33] , potentially reducing their relevance to vaccine development strategies. Moreover, MPER-specific mAbs have features that suggest they are products of autoreactive B cells, casting doubts over the possibility of inducing such antibodies by vaccination [34] . A fourth target of neutralizing mAbs is the V3 loop, which is immunogenic but also a highly variable region involved in Env-coreceptor binding. Antibodies to the V3 loop, such as mAbs 447-52D and F425-B4E8, are mostly effective against neutralization sensitive (Tier-1) viruses and have generally a limited breadth of reactivity almost exclusively specific for clade B viruses, reflecting their provenance from clade B-infected individuals [11, 35, 36, 37] . A cluster of human V3 mAbs raised from B cells derived from non-B cladeinfected individuals showed variable neutralizing activity for two AG and two C clade primary isolates, although these were particularly neutralization sensitive [38] . Finally, the CD4-induced (CD4i) site has been described as a neutralization epitope primarily on Tier-1 isolates with limited accessibility on Tier-2 isolates [39] . Very recently, the isolation and partial characteriza-tion of two related MAbs from a clade A-infected donor that appear to have very broad and potent neutralization profiles was reported [40] . These MAbs recognize a discontinuous epitope only expressed on the native Env trimer, made up of segments of the CD4i, V2 and V3 loops. This publication is the first to provide new broadly neutralizing reagents from a non-clade B donor and provides proof-of-principle that new neutralization specificities remain to be discovered on HIV-1 Env.