[PDF][PDF] Overcoming steric restrictions of VRC01 HIV-1 neutralizing antibodies through immunization

KR Parks, AJ MacCamy, J Trichka, M Gray, C Weidle… - Cell reports, 2019 - cell.com
KR Parks, AJ MacCamy, J Trichka, M Gray, C Weidle, AJ Borst, A Khechaduri, B Takushi…
Cell reports, 2019cell.com
Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They
are derived from VH1-2∗ 02 antibody heavy chains paired with rare light chains expressing
5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet
been elicited by immunization. Env-derived immunogens capable of binding the germline
forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in
knockin mice. However, the elicited antibodies cannot bypass glycans present on the …
Summary
Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They are derived from VH1-202 antibody heavy chains paired with rare light chains expressing 5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in knockin mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that leads to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies.
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