Human immunodeficiency virus type 1 (HIV-1) vaccine immunogens capable of inducing broadly neutralizing antibodies (bNAbs) remain obscure. HIV-1 evades immune responses through enormous diversity and hides its conserved vulnerable epitopes on the envelope glycoprotein (Env) by displaying an extensive immunodominant glycan shield. In elite HIV-1 viremic controllers, glycan-dependent bNAbs targeting conserved Env epitopes have been isolated and are utilized as vaccine design templates. However, immunological tolerance mechanisms limit the development of these antibodies in the general population. The well characterized bNAbs monoclonal variants frequently exhibit extensive levels of somatic hypermutation, a long third heavy chain complementary determining region, or a short third light chain complementarity determining region, and some exhibit poly-reactivity to autoantigens. This review elaborates on the obstacles to engaging and manipulating the Env glycoprotein as an effective immunogen and describes an alternative reverse vaccinology approach to develop a novel category of bNAb-epitope-derived non-cognate immunogens for HIV-1 vaccine design.

• Keywords
• Broadly neutralizing antibodies, Combinatorial protein library, Glycans, HIV-1 vaccine, Non-cognate ligands, Protein mimicry,
• MeSH
• Epitopes immunology   MeSH
• env Gene Products, Human Immunodeficiency Virus immunology   MeSH
• HIV Infections immunology   MeSH
• HIV Antibodies * immunology   MeSH
• HIV-1 * immunology   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Mimicry immunology   MeSH
• Antibodies, Neutralizing * immunology   MeSH
• Polysaccharides immunology   MeSH
• AIDS Vaccines * immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Epitopes MeSH
• env Gene Products, Human Immunodeficiency Virus MeSH
• HIV Antibodies * MeSH
• Ligands MeSH
• Antibodies, Neutralizing * MeSH
• Polysaccharides MeSH
• AIDS Vaccines * MeSH

HIV-1 envelope (Env) N-glycosylation impact virus-cell entry and immune evasion. How each glycan interacts to shape the Env-protein-sugar complex and affects Env function is not well understood. Here, analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation sites affected the Env structure at distant locations and had a ripple effect on Env-wide glycan processing, virus infectivity, antibody recognition, and virus neutralization. Specifically, the N262 glycan, although not in the CD4-binding site, modulated Env binding to the CD4 receptor, affected Env recognition by several glycan-dependent neutralizing antibodies, and altered site-specific glycosylation heterogeneity, with, for example, N448 displaying limited glycan processing. Molecular-dynamic simulations visualized differences in glycan density and how specific oligosaccharide positions can move to compensate for a glycan loss. This study demonstrates how changes in individual glycans can alter molecular dynamics, processing, and function of the Env-glycan shield.

• Keywords
• Biochemistry, Biological Sciences, Glycobiology, Microbiology, Virology,
• Publication type
• Journal Article MeSH