Exploring the role of the “glycan-shield” of human immunodeficiency virus in susceptibility to, and escape from, broadly neutralising antibodies
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Date
2018
Authors
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Publisher
University of the Western Cape
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. Despite the importance of the HIV-
1 Env glycans, limited computational analyses have been employed to analyse these
glycans.
Here, the Env glycans of two HIV-1 wild-type subtype C isolates are examined, in
detail, using computational approaches. These particular strains were used since in
vitro data showed that the removal of a single glycan had a substantially different
impact on the neutralisation sensitivity of the two strains. Molecular dynamics
simulations, and the subsequent analyses, were carried out on the computationally
determined, fully glycosylated, Env structures of these two wild-type strains and their
N301A mutant counterparts.
Detailed comparison of the molecular dynamics simulations demonstrated that unique
glycan dynamics and conformations emerged and that, despite shared HXB2
reference sequence positions, the glycans adopted distinct conformations specific to
each wild-type model. Furthermore, different changes in conformations were observed
for each wild-type model compared to its N301A mutant counterpart and, interestingly,
these N301A mutant model-specific glycan conformations were directly associated
with the protein residues ultimately found to be exposed, which may explain the varied
resistance to neutralising antibodies observed, in vitro, for the two N301A mutant
strains.
Description
Philosophiae Doctor - PhD
Keywords
HIV-1, Glycans, Antibodies, Neutralisation resistance, Molecular dynamics