Anti-HIV bNAbs were discovered in the early 1990s when researchers found antibodies capable of neutralizing different virus subtypes [
13]. Characterization of these responses has shown the bNAbs target sites include the conserved regions near the CD4 binding site (CD4bs) [
13], the membrane-proximal external region (MPER) [
14], and the base of the V3 and V1/V2 loops [
15] of which some bNAbs are glycan-dependent [
16‐
18]. Despite the early discovery of broadly neutralizing anti-HIV antibodies (bNAbs), including 447-52D (V3 loop), b12 (CD4 binding site), 17b (co-receptor binding site), 2G12 (viral glycan), 4E10 and 2F5 (gp41 MPER), enthusiasm for an Ab-based vaccine was limited based on the unusual characteristics of these bNAbs: 2G12 has three antigen combining sites, instead of the usual two [
19]; 2F5 and 4E10 are self-reactive [
20,
21]; and b12 is a phage-derived Ab generated by random pairing of heavy and light chains that may have never existed in nature [
22]. However, recent development of single-cell antibody cloning techniques applied to plasma B cells of HIV infected patients uncovered variety of new bNAbs (Table
1), and detailed analyses of these antibodies indicated they are approximately 10- to 100-fold more potent and have an increased breadth compared with the original 4 isolates [
23,
24]. To date, there have been a few clinical trials with anti-HIV bNAbs that are successful in reducing viral loads, most notably with 3BNC117 (a CD4bs-specific antibody) currently in phase 2 clinical trials [
3‐
5]. Other studies also showed that passive infusion of NAbs could effectively protect macaques from vaginal SHIV challenge [
25,
26]. These results suggest a role of Abs in HIV protection and control, but HIV has a tendency to accumulate mutations, making it a difficult target in vaccination strategies. Epitope mapping of the new, potent antibodies has invigorated the vaccine field by providing precise regions to target when designing new protein or subunit vaccine antigens to induce bNAbs [
27]. However, even with this new wealth of information at hand, generating bNAbs with improved, redesigned antigens still prove to be problematic, and there are no appropriate immunogens/vaccination strategies that have been discovered to elicit an effectively protective Ab response.
Table 1
Characteristics of anti-HIV bNAbs
CD4bs | b12a
| 35–75 | 2.82 | 18 | 17.3 | 1991 |
HJ16 | 36 | 8.01 | 21 | 36.7 | 2010 |
VRC01 | 88–93 | 0.09 | 14 | 38.8 | 2010 |
VRC02 | 90–91 | 0.13 | 14 | 34.9 | 2010 |
VRC03 | 51–59 | 0.08 | 16 | 34.9 | 2010 |
PGV04 | 77–88 | 0.14 | 16 | 38.2 | 2011 |
CH31 | 84–91 | 0.02 | 15 | 31.9 | 2011 |
CH33 | 90 | 0.24 | 15 | 31.9 | 2011 |
NIH45-46 | 84–86 | 0.08 | 18 | 44 | 2011 |
3BNC117 | 86–92 | 0.06 | 12 | 36.9 | 2011 |
12A12 | 92–96 | 0.07 | 15 | 34 | 2011 |
VRC23 | 65–80 | 0.58 | | | 2013 |
V1/V2 loop | PG9 | 77–83 | 0.08 | 30 | 15.4 | 2009 |
PG16 | 73–79 | 0.02 | 30 | 16.8 | 2009 |
PG145 | 78 | 0.29 | 33 | 22.8 | 2011 |
CH01 | 46 | 3.75 | 24 | 23.3 | 2011 |
V1/V2 loop | 2G12a
| 28–39 | 1.45 | 16 | 33.6 | 1994 |
PGT121 | 70 | 0.03 | 26 | 21.2 | 2011 |
PGT128 | 72 | 0.02 | 21 | 27.9 | 2011 |
CD4i/V3 | 3BC176 | 64 | 12.8 | 19 | 29.4 | 2012 |
gp41 MPER | 2F5a
| 55–67 | 1.44 | 24 | 15.2 | 1992 |
4E10a
| 85–100 | 1.62 | 20 | 15.6 | 1994 |
Z13 | 35 | 40 | 19 | 21 | 2001 |
10E8 | 98–99 | 0.25 | 22 | 22.1 | 2012 |
gp120/gp41 | PGT151-155 | 64–66 | 0.008–0.012 | 28 | | 2014 |
Interface | Interface | 67 | 0.87 | 9 | | 2011 |