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.

Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection

“…Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing antibodies (bNAbs) may facilitate new approaches for HIV-1 prevention, treatment, or even cure ( 1 , 2 ). bNAbs can neutralize a variety of circulating HIV-1 strains and are naturally produced in a small set of infected individuals ( 3 ). Innovative research has led to the development of bNAbs with improved features such as longer half-lives, favorable safety profiles ( 2 , 4 , 5 ), and potential to engage other components of the host immune response ( 6 , 7 ).…”

“…These bNAbs primarily target the trimeric HIV-1 envelope (Env) glycoprotein heterodimers ( 8 , 9 ). Six bNAb categories based on recognition of the following distinct and largely conserved epitopes on the Env glycoprotein have been characterized: the V1/V2 loop at the trimer apex, the V3 region, the CD4 binding site (CD4bs), the membrane-proximal external region (MPER), the gp120/gp41 interface, and the fusion peptide ( 3 , 10 – 13 ). Diverse antibodies provide insights for rational vaccine and immunogen design because they have different biophysical properties that may translate into variable potency or breadth, even when they target the same epitope ( 14 , 15 ).…”

A calculated risk: Evaluating HIV resistance to the broadly neutralising antibodies10-1074 and 3BNC117

“…3BNC117 is a VRC01-class bNAb that mimics CD4 binding [ 27 ] CD4 binding site bNAb epitopes need to be conserved and lie within an HIV Env cavity, protected by the Env V1V2 and V3 regions and the glycan shield [ 28 ]. The contact residues of 3BNC117 on Env are located in Loop D, the CD4 binding loop and the β23 V5 loop (HXB2 amino acid positions 274–283, 364–374 and 455–471, respectively) [ 9 , 14 ].…”

Biotinylation Eliminates the Intermediate State of Top7 Designed with an HIV-1 Epitope

“…Many broadly neutralizing antibodies were isolated in which most of them act against two HIV-1 envelope glycoproteins: the external gp120 and the virus transmembrane gp41 . In addition to this scarcity, monoclonal antibodies have a specific mechanism of interaction with the moving target envelope proteins, which makes the improvement of current combinations of antiretroviral therapies and clinically potential vaccines difficult . Structural combined with computational biology has provided a bypass to manipulate protein antigens that precisely replicates the antigenic surface recognized by the target antibody epitope with unprecedented atomic-level resolution. , …”