An MPER antibody neutralizes HIV-1 using germline features shared among donors

Abstract

The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. Here we describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. A recombinant sublineage variant pan-neutralizes a 130-isolate panel at 1.4 μg/ml (IC50). Notably, a germline revertant with mature CDR3s neutralizes 12% of viruses and still binds MPER after DJ reversion. Crystal structures of lipid-bound PGZL1 variants and cryo-EM reconstruction of an Env-PGZL1 complex reveal how these antibodies recognize MPER and viral membrane. Discovery of common genetic and structural elements among MPER antibodies from different patients suggests that such antibodies could be elicited using carefully designed immunogens.

Major Scientific Hurdles in HIV Vaccine Development: Historical Perspective and Future Directions

“…The discovery of human sera from HIV infected individuals that could neutralize a broad range of lab-adapted HIV-1 strains led to the rapid isolation and characterization of bNAbs (139)(140)(141)(142). From then on, numerous bNAbs have been isolated, some of which can neutralize up to 99% of all known HIV-1 isolates (143). It is now well established that bNAbs responses can be generated during natural infection, but are quite rare and tend to occur much later in chronic infection (144,145).…”

Neutralizing Antibodies Targeting HIV-1 gp41

“…Z13E binds to an S-shaped epitope that overlaps with that of 2F5 and 4E10 [ 37 , 72 ]. Abs 4E10 [ 35 , 72 , 73 ] ( Figure 2 C), 10E8 [ 36 ] ( Figure 2 D), CAP206-CH12 [ 74 ], DH511 [ 38 ] ( Figure 2 E), VRC42 [ 39 ] ( Figure 2 F), LN01 [ 40 ] ( Figure 2 G), and PGZL1 [ 41 ] ( Figure 2 H) recognize linear sequences forming helical epitopes adjacent to the transmembrane region (TM). Recent studies suggest that the MPER epitope extends into the TM since LN01 requires the first helical turn of the TM for interaction [ 40 ] and the binding affinity of 10E8 increases in the presence of TM [ 75 ], consistent with increased 4E10 binding in the presence of TM [ 76 ].…”

“…4E10 can bind to lipid components such as glycerol-1-phosphate, glycerol-3-phosphate, phosphatidic acid and phosphatidylglycerol ( Figure 5 A) [ 119 ], 10E8 interacts with glycerol, phosphatidylglycerol and phosphatidic acid ( Figure 5 B) [ 120 ] and LN01 with phosphatidylserine and the phosphocholine group of Fos-choline-12 mimicking a phospholipid interaction ( Figure 5 C) [ 40 ]. Furthermore, PGZL1 and its variant H4K3 coordinate two phosphatidic acid molecules [ 41 ] ( Figure 5 D). To further increase membrane interaction with negatively charged phospholipids basic patches are present in the 10E8 light chain that are positioned at the putative Fab-membrane interface, which are either germline encoded or generated by somatic mutations.…”

“…Notably, a germline revertant of PGZL1 with mature CDR3s still neutralizes 12% of a 130-isolate panel. As an exception, the complete germline reversion of PGZL1 still binds MPER [ 41 ] providing a starting point to specifically activate naïve B cells by immunization.…”

“…This led to the discovery of a plethora of antibodies targeting many exposed regions of the prefusion Env trimer and in turn accelerated the structural characterization and optimization of Env-based immunogens [ 17 , 18 ]. Key structures of bnAbs target V1/V2 [ 19 , 20 , 21 ], glycan-V3 [ 22 , 23 , 24 ], the CD4-binding site [ 25 , 26 , 27 , 28 , 29 ], the fusion peptide [ 11 , 30 ], the gp120/gp41 interface [ 31 , 32 ], the silent face of gp120 [ 33 ], the N-terminal region of the gp41 membrane-proximal external region (MPER) [ 34 ] as well as C-terminal MPER [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Structural biology together with longitudinal studies on B cell linage development has played a central role in understanding the role of somatic hypermutation in the generation of broadly neutralizing antibodies.…”