title: A single residue within the V5 region of HIV-1 envelope facilitates viral escape from the broadly neutralizing monoclonal antibody VRC01.
abstract: VRC01, a broadly neutralizing monoclonal antibody, is capable of neutralizing a diverse array of HIV-1 isolates by mimicking CD4 binding with the envelope glycoprotein gp120. Nonetheless, resistant strains have been identified. Here, we examined two genetically related and two unrelated envelope clones, derived from CRF08_BC-infected patients, with distinct VRC01 neutralization profiles. A total of 22 chimeric envelope clones was generated by interchanging the loop D and/or V5 regions between the original envelopes or by single alanine substitutions within each region. Analysis of pseudoviruses built from these mutant envelopes showed that interchanging the V5 region between the genetically related or unrelated clones completely swapped their VRC01 sensitivity profiles. Mutagenesis analysis revealed that the asparagine residue at position 460 (Asn-460), a potential N-linked glycosylation site in the V5 region, is a key factor for observed resistance in these strains, which is further supported by our structural modeling. Moreover, changes in resistance were found to positively correlate with deviations in VRC01 binding affinity. Overall, our study indicates that Asn-460 in the V5 region is a critical determinant of sensitivity to VRC01 specifically in these viral strains. The long side chain of Asn-460, and potential glycosylation, may create steric hindrance that lowers binding affinity, thereby increasing resistance to VRC01 neutralization.
authors.affiliation: AIDS Research Center, MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Dongxing
authors.initials: D
authors.lastname: Guo
authors.forename: Xuanling
authors.initials: X
authors.lastname: Shi
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Arledge
authors.forename: Dingka
authors.initials: D
authors.lastname: Song
authors.forename: Liwei
authors.initials: L
authors.lastname: Jiang
authors.forename: Lili
authors.initials: L
authors.lastname: Fu
authors.forename: Xinqi
authors.initials: X
authors.lastname: Gong
authors.forename: Senyan
authors.initials: S
authors.lastname: Zhang
authors.forename: Xinquan
authors.initials: X
authors.lastname: Wang
authors.forename: Linqi
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001216:Asparagine / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D005838:Genotype; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology*; D019302:HIV Envelope Protein gp160 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D001216:Asparagine; C481504:ibalizumab