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. 2015 Aug;89(15):8003-10.
doi: 10.1128/JVI.00754-15. Epub 2015 May 27.

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

Ruimin Pan  1 , Miroslaw K Gorny  2 , Susan Zolla-Pazner  3 , Xiang-Peng Kong  4
Affiliations

The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

Ruimin Pan et al. J Virol. 2015 Aug.

Abstract

The region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2ZM109-1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. The epitope of monoclonal antibody 830A is discontinuous and composed of three segments: (i) Thr175, Tyr177, Leu179, and Asp180 at the kink overlapping the integrin-binding site; (ii) Arg153 and Val154 in V1; and (iii) Ile194 at the C terminus of V2. This report thus provides the atomic details of the immunogenic "V2i epitope."

Importance: Data from the RV144 phase III clinical trial suggested that the presence of antibodies to the first and second variable regions (V1V2) of gp120 was associated with the modest protection afforded by the vaccine. V1V2 is a highly variable and immunogenic region of HIV-1 surface glycoprotein gp120, and structural information about this region and its antigenic landscape will be crucial in the design of an effective HIV-1 vaccine. We have determined a crystal structure of V1V2 in complex with human MAb 830A and have shown that MAb 830A recognizes a region overlapping the α4β7 integrin-binding site. We also showed that V1V2 forms a 5-stranded beta barrel, an elegant structure allowing sequence variations in the strand-connecting loops while preserving a conserved core.

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Figures

FIG 1
FIG 1
Structure of Fab 830A in complex with V1V2ZM109-1FD6. (A) Molecules in the asymmetric unit (ASU) represented as ribbons. There are two Fab 830A/V1V2ZM109-1FD6 complexes in the ASU: the two V1V2ZM109-1FD6 complexes are colored magenta and salmon, respectively, while the heavy chains of Fab 830A are colored green and light blue and the light chains are colored cyan and wheat, respectively. (B) One of the Fab 830A/V1V2ZM109-1FD6 complexes in a side view. Only the Fv region of 830A is shown, and the 1FD6 scaffold is colored gray. (C) Superimposition of the two V1V2s in the ASU. The five strands (A, B, C, C′, and D) and the short 310 helical turn (k, “kink”) are labeled. Note that the strands connecting the loop regions have slightly different conformations in the two molecules. (D) Superimposition of 830A-bound V1V2 (magenta) and PG9-bound V1V2 (gray). Note the extra C′ strand in 830A-bound V1V2.
FIG 2
FIG 2
Five-stranded V1V2ZM109 beta barrel. (A) The five-stranded beta barrel structure of V1V2. Regions missing in electron density in the two strand-connecting loops (SCLs) between strands A and B (SCLA-B) and between strands C′ and D (SCLC′-D) are represented by dashed lines and found at one end of the barrel. (B) A top view of the hydrophobic core. For clarity, only side chains of selected hydrophobic residues are shown. (C) A side view of the V1V2 barrel. Note the three observed glycans pointing toward one side of the barrel. (D) Alignment of V1V2 sequences. The amino acid profile of the 2013 premade envelope alignment of the LANL database sequences (http://www.hiv.lanl.gov) is shown. The size of each amino acid in the profile is drawn proportionally to its weight of conservation at the particular location. The V1V2 sequences of HXB2 and ZM109 are placed below the profile. The regions of beta strands observed in the crystal structure and the strand-connecting loops (SCLA-B and SCLC′-D) are illustrated by arrows and dashed lines, respectively.
FIG 3
FIG 3
Details of the antigen-antibody interactions. (A) Key residues of V1V2ZM109 recognized by Fab 830A. The side chains of residues with areas of contact with 830A that are more than 10 Å2 in size are shown. Note that two of the three integrin-binding site residues, LeuG179 and AspG180, are exposed and are part of the epitope of 830A. (B) Key residues of the 830A paratope. (C) Amino acids of the 830A epitope, with the size of each residue drawn proportionally to its area of contact with the antibody. (D) Schematic diagram of the antigen-antibody interaction. Hydrogen-binding interactions are indicated by dashed lines between the residues, while van der Waals contacts are represented by “eyelashes.” Residues in solid ovals contribute to the interactions by their main chain atoms, and those in dashed ovals contribute to the interactions by their side chain atoms. Residues in cyan and green are from the 830A light and heavy chains, respectively.
FIG 4
FIG 4
Topology of V1V2 and location of 830A epitope in the trimer context. (A) The topology of V1V2ZM109. Regions of the 830A epitope are indicated by green dashed circles. The locations of the six glycosylation sites in V1V2ZM109 (only three were observed in the 830A complex) are indicated by brown diamonds. The pink dashed line depicts the connection of strand C with the kink. (B) The location of the 830A epitope in the context of the BG505 SOSIP.664 prefusion trimer (PDB ID 4TVP). The trimeric complex of gp120 (green) and gp41 (orange) is viewed from the side, and regions V1V2 and V3 of one of the gp120s are colored magenta and blue, respectively. The 830A epitope is shown as a green surface, while the PG9 epitope is also shown as a gray surface (for simplicity, the glycans are not displayed).
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