Neutralization sensitivity and immune escape of HIV-1 CNS related mutations

Objective To investigate neutralization sensitivity of HIV-1 pseudoviruses with CNS related mutations on broadly monoclonal neutralizing antibodies (bmNAbs), and to explore the possibility of immune escape. Methods The pseudoviruses with HIV-1 CNS related mutations, including S446T, F396N, K429G, K337G, T319A, Q389K and N407T were constructed. The corresponding infectivity of above mutants, and the neutralization sensitivity in responding to bmNAbs, e.g. PGT121、PGT135、VRC01、2G12、10E8 and 12A21 were determined. Molecular docking was used to explore the effects of CNS-related residues of env proteins on antibody binding. Results All the pseudoviruses carrying 7 mutations were highly sensitive to neutralization by VRC01, 2G12 and 10E8, but were resistant to PGT121 and 12A21. As for PGT135, the pseudovirus containing the F396N mutant displayed highly sensitive to it, and S446T, K429G and T319A mutants showed moderately sensitive to this mutation type, but K337G, Q389K and N407T were resistant to PGT135. When the molecular conformational simulation of Q389 mutated to K, the hydrogen bond formed between the nitrogen atom of Q389 NE2 and the oxygen atom of T415 disappeared. The folding of the amino acid side chain may strengthen in steric hindrance, affecting the residue at position 389 as a contactable residue to interaction with PGT135. Conclusions HIV-1 pseudovirus with CNS-related mutations may undergo immune escape, which reduced neutralization sensitivity to PGT135 in some degree.. Key words: HIV-1; CNS; gp120; immune escape; neutralization