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. 2015 Oct-Dec;7(4):11-21.

Broadly Neutralizing Antibodies against HIV-1 As a Novel Aspect of the Immune Response

D N Shcherbakov  1 , A Y Bakulina  2 , L I Karpenko  3 , A A Ilyichev  3
Affiliations

Broadly Neutralizing Antibodies against HIV-1 As a Novel Aspect of the Immune Response

D N Shcherbakov et al. Acta Naturae. 2015 Oct-Dec.

Abstract

The human immunodeficiency virus-1 (HIV-1) has the ability to evade the adaptive immune response due to high mutation rates. Soon after the discovery of HIV-1, it was originally proposed that neutralizing of antibodies to the virus occurs rarely or cannot be elicited at all. In the 1990s, there appeared reports that sera of select HIV-1-infected individuals contained antibodies capable of neutralizing different virus subtypes. Such antibodies were named broadly neutralizing antibodies (bNAbs). Since 2009, the development of new cell technologies has intensified research efforts directed at identifying new bNAbs with a neutralization potency of over 90% of primary HIV-1 isolates. These antibodies have unique characteristics which include high levels of somatic mutations and unusually long variable loops that penetrate through the glycan shield of HIV-1 Env to contact the protein surface. In this review, we will attempt to summarize the latest data on bNAbs against HIV-1 in terms of their interactions with the sites of vulnerability on HIV-1 glycoproteins.

Keywords: Broadly neutralizing antibodies; HIV-1; bNAbs; gp120; gp41.

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Figures

Fig. 1
Fig. 1
Trimeric Env interaction with the host cell membrane is illustrated. The gp120 subunit binds to the CD4 receptors, triggering conformational rearrangements to unmask the coreceptor binding site originally hidden by the V3 and V1/V2 loops. Engagement with CCR5 or the other coreceptor drives viral fusion and entry
Fig. 2
Fig. 2
Schematic of the trimeric HIV-1 envelope glycoprotein structure and sites of vulnerability recognized by bNAbs are shown. The α-helixes are shown with cylinders, β-sheets, with arrows; loops, with thin lines; glycosylated amino acid residues, with circles. Detailed characteristics of bNAbs are given in Table. A – CD4bs on gp120 is involved in CD4 atachment. The major epitopes are the D loop, the V1/V2 loops, the V5 loops and the flanking β-sheets 23 and 24, an epitope within β-sheet 15, the α-helix3, and an epitope within β-sheet 16. The epitope structure is reconstituted based on data from [13]. B – the epitope made up of V1/V2. The antibody recognition site is a region in a β-conformation, including glycans at N156 and N160. The epitope structure is drawn based on Ref [14]. C – the epitope is on gp120. The sites involved in binding are: regions of β-sheets 19, 17, 13, V3, and V4 regions, 4 and 3 α-helixes, glycans at N392, N386, N339, N332, N301, and N295. The epitope structure is drawn based on Ref [15]. D – MPER-site, a linear epitope on gp41. A region within the MPER-site is amenable to recognition The epitope structure is drawn based on Ref [16]. E – the epitope at the gp120/ gp41 interface. N-linked glycans within gp41, a glycan moiety at N637, N276, and N234 V5 and D regions are targeted. The epitope structure is drawn based on Ref [17]
Fig. 3
Fig. 3
The PG9 Fab-fragment in complex with HIV-1 gp120 is shown. The variable and conserved domains of the heavy and light chains are in green and grey, respectively. The extended CDR H3 loop reaching through to the gp120 surface is highlighted. The β-sheets of CDR H3, critical for binding, are in red. The N-glycans at N160 and N156 through which the PG9 CDR H3 penetrates are shown as blue clouds. The schematic is reproduced based on the structures of 3U4E and 3DNN from Protein Data Bank
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