Abstract
During the entry process, the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer undergoes a sequence of conformational changes triggered by both CD4 and coreceptor engagement. Resolving the conformation of these transient entry intermediates has proven challenging. Here, we fine-mapped the antigenicity of entry intermediates induced by increasing CD4 engagement of cell surface–expressed Env. Escalating CD4 triggering led to the sequential adoption of different pre-fusion conformational states of the Env trimer, up to the pre-hairpin conformation, that we assessed for antibody epitope presentation. Maximal accessibility of the coreceptor binding site was detected below Env saturation by CD4. Exposure of the fusion peptide and heptad repeat 1 (HR1) required higher CD4 occupancy. Analyzing the diverse antigenic states of the Env trimer, we obtained key insights into the transitions in epitope accessibility of broadly neutralizing antibodies (bnAbs). Several bnAbs preferentially bound CD4-triggered Env, indicating a potential capacity to neutralize both pre- and post-CD4 engagement, which needs to be explored. Assessing binding and neutralization activity of bnAbs, we confirm antibody dissociation rates as a driver of incomplete neutralization. Collectively, our findings highlight a need to resolve Env conformations that are neutralization-relevant to provide guidance for immunogen development.
Highlights
Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimers, composed of three gp41-gp120 heterodimers, initiate the virus entry process by binding to the primary receptor CD4 via a high-affinity binding site on gp120
third hypervariable (V3) crown and CD4-induced site (CD4i) antibodies are abundant in HIV-1 infection but have only a weak or no detectable neutralization activity at all because of their limited capacity to access their epitopes on the closed Env trimer [9,10,11,12]
The capacity to bind to the closed Env is generally thought to be critical for HIV-1 neutralizing antibody activity [4,15,16,17], the precise modes of action differ between individual nAbs and include direct interference with CD4 or coreceptor engagement [18,19], arrest of Env in the ground state [4,5,20], or acceleration of trimer decay by capturing Env in an activated state [4,21,22,23]
Summary
Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimers, composed of three gp41-gp120 heterodimers, initiate the virus entry process by binding to the primary receptor CD4 via a high-affinity binding site (referred to as CD4bs) on gp120. CD4 triggering exposes neutralization-vulnerable epitopes shielded on the native trimer, including the third hypervariable (V3) loop crown and the CD4-induced site (CD4i) [6,7,8]. The capacity to bind to the closed (preCD4-bound) Env is generally thought to be critical for HIV-1 neutralizing antibody (nAb) activity [4,15,16,17], the precise modes of action differ between individual nAbs and include direct interference with CD4 or coreceptor engagement [18,19], arrest of Env in the ground state [4,5,20], or acceleration of trimer decay by capturing Env in an activated state [4,21,22,23]
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