Abstract
Variable V1/V2 and V3 loops on human immunodeficiency virus type 1 (HIV-1) envelope-gp120 core play key roles in modulating viral competence to recognize two infection receptors, CD4 and chemokine-receptors. However, molecular bases for the modulation largely remain unclear. To address these issues, we constructed structural models for a full-length gp120 in CD4-free and -bound states. The models showed topologies of gp120 surface loop that agree with those in reported structural data. Molecular dynamics simulation showed that in the unliganded state, V1/V2 loop settled into a thermodynamically stable arrangement near V3 loop for conformational masking of V3 tip, a potent neutralization epitope. In the CD4-bound state, however, V1/V2 loop was rearranged near the bound CD4 to support CD4 binding. In parallel, cell-based adaptation in the absence of anti-viral antibody pressures led to the identification of amino acid substitutions that individually enhance viral entry and growth efficiencies in association with reduced sensitivity to CCR5 antagonist TAK-779. Notably, all these substitutions were positioned on the receptors binding surfaces in V1/V2 or V3 loop. In silico structural studies predicted some physical changes of gp120 by substitutions with alterations in viral replication phenotypes. These data suggest that V1/V2 loop is critical for creating a gp120 structure that masks co-receptor binding site compatible with maintenance of viral infectivity, and for tuning a functional balance of gp120 between immune escape ability and infectivity to optimize HIV-1 replication fitness.
Highlights
An envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is synthesized in cells as a precursor gp160, and subsequently cleaved to mature gp120 and gp41
Because full-length gp120 structures of the same strain in CD4free and -bound states were unavailable at atomic levels in the public database, we constructed them with the aid of in silico science
Cell-based adaptation experiments led to the identification of single amino acid substitutions in Env gp120 for enhanced viral entry/growth through better affinity for CCR5 (Figures 4–6)
Summary
An envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is synthesized in cells as a precursor gp160, and subsequently cleaved to mature gp120 and gp. HIV-1 Env works, as a trimer of a gp120-gp dimer molecule, on viral entry into target host cells (Freed and Martin, 1995, 2013; Clapham and McKnight, 2002; Wilen et al, 2012). Env-gp120 binds to receptor CD4 and co-receptor CCR5 or CXCR4, whereas Env-gp mediates virus-cell membrane fusion. Depending on the co-receptor usage, HIV-1 strains are grouped into CCR5 (R5)-tropic and CXCR4. Viral Env proteins undergo large conformational changes. CD4 induces gp120 conformational change upon their binding, and facilitates subsequent interaction with the co-receptor. Binding of gp120 to the receptor and co-receptor triggers a drastic structural change of gp, and allows virus-cell membrane fusion.
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