Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers

• Published in: Frontiers in immunology Vol. 12; p. 670561
• Main Authors: Nyanhete, Tinashe E, Edwards, Robert J, LaBranche, Celia C, Mansouri, Katayoun, Eaton, Amanda, Dennison, S Moses, Saunders, Kevin O, Goodman, Derrick, Janowska, Katarzyna, Spreng, Rachel L, Zhang, Lu, Mudrak, Sarah V, Hope, Thomas J, Hora, Bhavna, Bradley, Todd, Georgiev, Ivelin S, Montefiori, David C, Acharya, Priyamvada, Tomaras, Georgia D
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.12.2021
• Subjects: Antibody Specificity; antibody-dependent cellular phagocytosis (ADCP); Binding Sites, Antibody; broadly neutralizing antibodies; Broadly Neutralizing Antibodies - immunology; CD4 Antigens - immunology; CD4 Antigens - metabolism; CD4 Lymphocyte Count; CD4-binding site antibodies; Epitope Mapping; Epitopes - immunology; Female; Genes, env; HIV Antibodies - immunology; HIV Envelope Protein gp120 - immunology; HIV Infections - immunology; HIV-1 - immunology; HIV-1 Virus Controllers; HLA-B Antigens - immunology; Humans; Immune Evasion; Immunoglobulin Fc Fragments - immunology; Immunoglobulin Fragments - immunology; Immunology; Male; Models, Molecular; negative-stain electron microscopy; neutralization fingerprinting assay; Peptide Fragments - immunology; Phagocytosis; Protein Domains; Recombinant Proteins - immunology; Survivors; Viral Load; Viremia - immunology; negative-stain electron microscopy; antibody-dependent cellular phagocytosis (ADCP); CD4-binding site antibodies; neutralization fingerprinting assay; broadly neutralizing antibodies; HIV-1 Virus Controllers
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.670561

Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy naïve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.