A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target

Abstract

Antibodies that can neutralize diverse HIV-1 strains develop in ~10-20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of broadly reactive antibodies in complex with the HIV-1 spike indicate that there are a limited number of sites of vulnerability on the spike. Analysis of their structures can help reveal commonalities that would be useful in vaccine design and provide insights on combinations of antibodies that can be used to minimize the incidence of viral resistance mutations. In this review, we give an update on recent structures determined of the spike in complex with broadly neutralizing antibodies in the context of all epitopes on the HIV-1 spike identified to date.

Keywords: HIV-1; envelope; epitope; neutralization; neutralizing antibodies; spike; structure.

Figure 1

HIV-1 Env structure and dynamics. (A) Domain architecture of HIV-1 Env, with the gp120 and gp41 domains highlighted. The furin cleavage site, fusion peptide (FP), heptad repeats 1 and 2 (HR1 and HR2), membrane proximal external region (MPER), transmembrane domain (TM), and cytoplasmic tail (CT), are shown. Glycosylation sites are numbered (based on the HXB2 strain) and marked with fork symbols. (B) Viral entry. The gp41 (yellow) and gp120 (green) subunits are shown with their variable loops, V1V2 (cyan), V3 (purple), and V5 (white) in different conformations as they go through the fusion process. The fusion peptide (brown) and transmembrane domain (gray) are also shown. V4 is not shown in panel B, and the loops were excluded from the fusion panel for clarity. Binding partners on the host are shown, α₄β₇ (red, navy), CD4 (blue), and the coreceptor (orange).

Figure 2

HIV-1 Env glycan shield and broadly neutralizing epitopes. Surface representation of the fully glycosylated BG505 HIV-1 Env (PDB ID: 5T3Z) is shown from different views along with glycans (green spheres labeled with the amino acid that is glycosylated) and broadly neutralizing antibody epitopes colored based on site: CD4bs (yellow), V1V2 (red), V3 glycan supersite (blue), silent face (orange), gp120–gp41 interface (purple), and the gp41 FP (cyan) and a portion of the MPER (salmon).

Figure 3

Complexes between bnAbs and HIV-1 Env. Top and side views of CD4 (yellow, PDB ID: 1GC1) in complex with the Env trimer (gray, PDB ID: 5T3Z) are shown for reference along with CD4bs bnAbs VRC01 (blue, PDB ID: 4LST), CH103 (orange, PDB ID: 4JAN), and M1214-N1 (magenta, PDB ID: 6VY2) below. Of the V1V2 apex bnAbs structurally characterized to date, CAP256-VRC26.25 (teal, PDB ID: 6VTT), VRC38 (purple, PDB ID: 5VGJ), and PGT145 (orange, PDB ID: 5V8L) are shown. Of the V3 glycan supersite bnAbs structurally characterized to date, DH270.6 (cyan, PDB ID: 6UM6), 438-B11 (red, PDB ID: 6UTK), and Ab1485 (purple, 7KDE) are shown. The two known silent face bnAbs SF12 (magenta, PDB ID: 6OKP) and VRC-PG05 (yellow, PDB ID: 6BF4) are shown. Of the gp120–gp41 interface bnAbs structurally characterized to date, 8ANC195 (teal, PDB ID: 5CJX), 35O22 (magenta, PDB ID: 4TVP), and 1C2 (orange, PDB ID: 6P65) are shown. Only gp41 FP-directed bnAbs VRC34 (blue, PDB ID: 6NC3), ASC202 (yellow, PDB ID: 6NC2), and PGT151 (magenta, PDB ID: 6DCQ) are shown; MPER-directed bnAbs clash with a closed trimer and are therefore not shown. Relevant glycans are shown as green sticks and labeled according to the amino acid that is glycosylated. For clarity, only the Fv region of the antibodies is shown on a single protomer of the trimer, even if additional copies can bind. Side (left) and bottom or top (right) views are shown.

Figure 3

Complexes between bnAbs and HIV-1 Env. Top and side views of CD4 (yellow, PDB ID: 1GC1) in complex with the Env trimer (gray, PDB ID: 5T3Z) are shown for reference along with CD4bs bnAbs VRC01 (blue, PDB ID: 4LST), CH103 (orange, PDB ID: 4JAN), and M1214-N1 (magenta, PDB ID: 6VY2) below. Of the V1V2 apex bnAbs structurally characterized to date, CAP256-VRC26.25 (teal, PDB ID: 6VTT), VRC38 (purple, PDB ID: 5VGJ), and PGT145 (orange, PDB ID: 5V8L) are shown. Of the V3 glycan supersite bnAbs structurally characterized to date, DH270.6 (cyan, PDB ID: 6UM6), 438-B11 (red, PDB ID: 6UTK), and Ab1485 (purple, 7KDE) are shown. The two known silent face bnAbs SF12 (magenta, PDB ID: 6OKP) and VRC-PG05 (yellow, PDB ID: 6BF4) are shown. Of the gp120–gp41 interface bnAbs structurally characterized to date, 8ANC195 (teal, PDB ID: 5CJX), 35O22 (magenta, PDB ID: 4TVP), and 1C2 (orange, PDB ID: 6P65) are shown. Only gp41 FP-directed bnAbs VRC34 (blue, PDB ID: 6NC3), ASC202 (yellow, PDB ID: 6NC2), and PGT151 (magenta, PDB ID: 6DCQ) are shown; MPER-directed bnAbs clash with a closed trimer and are therefore not shown. Relevant glycans are shown as green sticks and labeled according to the amino acid that is glycosylated. For clarity, only the Fv region of the antibodies is shown on a single protomer of the trimer, even if additional copies can bind. Side (left) and bottom or top (right) views are shown.