8TNH

Cryo-EM structure of HIV-1 Env BG505 DS-SOSIP in complex with broadly neutralizing llama nanobody G36 targeting the CD4-binding site

Summary for 8TNH

• Entry DOI: 10.2210/pdb8tnh/pdb
• EMDB information: 41415 41416 41417
• Descriptor: HIV-1 BG505 DS-SOSIP gp120, HIV-1 BG505 DS-SOSIP gp41, CD4-binding site nanobody G36, ... (7 entities in total)
• Functional Keywords: hiv-1 envelope, antibody, nanobody, vhh, llama, bg505 ds-sosip, neutralization, immunization, viral protein-immune system complex, viral protein/immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 9
• Total formula weight: 271276.37

Authors

Zhou, T.,Kwong, P.D.,Xu, J. (deposition date: 2023-08-01, release date: 2024-05-08, Last modification date: 2024-12-18)

Primary citation

Xu, J.,Zhou, T.,McKee, K.,Zhang, B.,Liu, C.,Nazzari, A.F.,Pegu, A.,Shen, C.H.,Becker, J.E.,Bender, M.F.,Chan, P.,Changela, A.,Chaudhary, R.,Chen, X.,Einav, T.,Kwon, Y.D.,Lin, B.C.,Louder, M.K.,Merriam, J.S.,Morano, N.C.,O'Dell, S.,Olia, A.S.,Rawi, R.,Roark, R.S.,Stephens, T.,Teng, I.T.,Tourtellott-Fogt, E.,Wang, S.,Yang, E.S.,Shapiro, L.,Tsybovsky, Y.,Doria-Rose, N.A.,Casellas, R.,Kwong, P.D.
Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1.
Adv Sci, 11:e2309268-e2309268, 2024

PubMed Abstract: Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean ICs of 0.314 and 0.033 µg mL, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals.

PubMed: 38704686
DOI: 10.1002/advs.202309268

Experimental method

ELECTRON MICROSCOPY (3.32 Å)