Structural Rearrangements Maintain the Glycan Shield of an HIV-1 Envelope Trimer After the Loss of a Glycan

Abstract

The HIV-1 envelope (Env) glycoprotein is the primary target of the humoral immune response and a critical vaccine candidate. However, Env is densely glycosylated and thereby substantially protected from neutralisation. Importantly, glycan N301 shields V3 loop and CD4 binding site epitopes from neutralising antibodies. Here, we use molecular dynamics techniques to evaluate the structural rearrangements that maintain the protective qualities of the glycan shield after the loss of glycan N301. We examined a naturally occurring subtype C isolate and its N301A mutant; the mutant not only remained protected against neutralising antibodies targeting underlying epitopes, but also exhibited an increased resistance to the VRC01 class of broadly neutralising antibodies. Analysis of this mutant revealed several glycans that were responsible, independently or through synergy, for the neutralisation resistance of the mutant. These data provide detailed insight into the glycan shield’s ability to compensate for the loss of a glycan, as well as the cascade of glycan movements on a protomer, starting at the point mutation, that affects the integrity of an antibody epitope located at the edge of the diminishing effect. These results present key, previously overlooked, considerations for HIV-1 Env glycan research and related vaccine studies.

Visualization of the HIV-1 Env glycan shield across scales

“…Computational modeling, in particular molecular dynamics (MD) simulations, has proven useful as a complementary approach for characterizing glycoprotein structure and dynamics (16)(17)(18)(19), including Env (6,(20)(21)(22). Three sets of atomistic dynamics simulations of fully glycosylated Env trimers were recently reported and these predicted that dynamics would lead to extensive shielding of the antigenic surface and the formation of extensive networks among interacting glycans (6,21,22).…”

Quantification of the Resilience and Vulnerability of HIV-1 Native Glycan Shield at Atomistic Detail

“…All previous computational studies have generalized glycan moieties as simple oligo-mannoses such as mannose-5 and mannose-9 [18, 35–37, 57] for the purpose of modeling. For the first time, we have incorporated native glycosylation, and included complex sugars based on site-specific mass spectrometry results.…”

“…Computational modeling and molecular dynamics (MD) simulations have been particularly useful as a complementary approach towards the characterization of such systems[31–34], and have been harnessed to study the conformational dynamics of the HIV Env glycan shield[18, 35–37]. However, the main drawback affecting the quality of MD simulations is the robustness of conformational sampling.…”

“…Recently there have been a few cryo-EM and X-ray structure determinations of natively glycosylated Env[54–56], however in these structures most of the glycans are not visible beyond the core glycan stem, unless stabilized by interactions with bound antibodies. Similarly, while a number of structural studies have been performed on the HIV-1 Env glycosylation using computational methods, all of these comprise of oligomannose glycan moieties ranging from mannose-5 to mannose-9[18, 35–37, 57]. Here, we have modeled the natively glycosylated Env, having both oligomannose and complex glycans[7, 58].…”

“…Using the natively glycosylated Env trimer of BG505 SOSIP, we have employed graph theory to capture the glycan shield topological network, pinpoint potential interaction pathways, and identify concerted behavior of the glycans. The glycan-glycan and glycan-protein interactions influence the behavior of the shield as a whole and can affect distant sites in the glycan network[7, 18, 35]. Such effects can be captured by this graph-based approach.…”