Abstract
BackgroundGlycans on the human immunodeficiency virus (HIV) envelope glycoprotein (Env) play an important role in viral infection and evasion of neutralization by antibodies. In this study, all 25 potential N-linked glycosylation sites (PNGS) on the HIV-1 CRF07_BC Env, FE, were mutated individually to study the effect of their removal on viral infectivity, virion production, and antibody-mediated neutralization.ResultsRemoval of specific N-glycosylation sites has a significant effect on viral infectivity and antibody-mediated neutralization phenotype. Six of these glycosylation mutants located on the V1/V2 and C1/C2 domains lost infectivity. PNGS mutations located on V4/C4/V5 (except N392 on V4), were shown to increase viral infectivity. Furthermore, FE is much more dependent on specific glycans than clade B Env YU-2. On neutralization effect, PNGS mutations at N197 (C2), N301 (V3), N442 (C4) and N625 (gp41) rendered the virus more susceptible to neutralization by the monoclonal antibodies (MAbs) that recognize the CD4 binding site or gp41. Generally, mutations on V4/V5 loops, C2/C3/C4 regions and gp41 reduced the neutralization sensitivity to PG16. However, mutation of N289 (C2) made the virus more sensitive to both PG9 and PG16. Furthermore, we showed that mutations at N142 (V1), N355 (C3) and N463 (V5) conferred resistance to neutralization by anti-gp41 MAbs. We used the available structural information of HIV Env and homology modeling to provide a structural basis for the observed biological effects of these mutations.ConclusionsThis report provides the first systematic experimental account of the biological role of the entire PNGS on an HIV-1 Env, which should provide valuable insights for understanding the function of Env in HIV infection cycle and for developing future anti-HIV strategies.
Highlights
Glycans on the human immunodeficiency virus (HIV) envelope glycoprotein (Env) play an important role in viral infection and evasion of neutralization by antibodies
potential N-linked glycosylation sites (PNGS) mutations and viral infectivity We showed that all Env mutations on or near the V1/V2 domain had no infectivity or a reduced viral infectivity
Our results indicated that wt and all PNGS mutants of FE were resistant to 2G12 at the highest concentration tested (25 μg/mL Monoclonal antibody (MAb))
Summary
Glycans on the human immunodeficiency virus (HIV) envelope glycoprotein (Env) play an important role in viral infection and evasion of neutralization by antibodies. All 25 potential N-linked glycosylation sites (PNGS) on the HIV-1 CRF07_BC Env, FE, were mutated individually to study the effect of their removal on viral infectivity, virion production, and antibody-mediated neutralization. HIV-1 gp120 is responsible for binding both the target cell CD4 receptor and co-receptors (CCR5 or CXCR4) [4,5], while gp, together with gp120, mediates fusion of the viral and host cell membranes for cell entry [6]. Structural forms that are necessary for viral-host membrane fusion [10,11]. This cascade of conformational changes leads to the exposure of new epitopes on gp120 and gp for antibodies to recognize. Owing to the steric and kinetic constraints caused by the continual structural rearrangements that occur, some of these epitopes are only transiently exposed
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