Rationally Targeted Mutations at the V1V2 Domain of the HIV-1 Envelope to Augment Virus Neutralization by Anti-V1V2 Monoclonal Antibodies.
HIV-1 envelope glycoproteins (Env) are the only viral antigens present on the virus surface and serve as the key targets for virus-neutralizing antibodies. However, HIV-1 deploys multiple strategies to shield the vulnerable sites on its Env from neutralizing antibodies. The V1V2 domain located at the apex of the HIV-1 Env spike is known to encompass highly variable loops, but V1V2 also contains immunogenic conserved elements recognized by cross-reactive antibodies. This study evaluates human monoclonal antibodies (mAbs) against V2 epitopes which overlap with the conserved integrin α4β7-binding LDV/I motif, designated as the V2i (integrin) epitopes. We postulate that the V2i Abs have weak or no neutralizing activities because the V2i epitopes are often occluded from antibody recognition. To gain insights into the mechanisms of the V2i occlusion, we evaluated three elements at the distal end of the V1V2 domain shown in the structure of V2i epitope complexed with mAb 830A to be important for antibody recognition of the V2i epitope. Amino-acid substitutions at position 179 that restore the LDV/I motif had minimal effects on virus sensitivity to neutralization by most V2i mAbs. However, a charge change at position 153 in the V1 region significantly increased sensitivity of subtype C virus ZM109 to most V2i mAbs. Separately, a disulfide bond introduced to stabilize the hypervariable region of V2 loop also enhanced virus neutralization by some V2i mAbs, but the effects varied depending on the virus. These data demonstrate that multiple elements within the V1V2 domain act independently and in a virus-dependent fashion to govern the antibody recognition and accessibility of V2i epitopes, suggesting the need for multi-pronged strategies to counter the escape and the shielding mechanisms obstructing the V2i Abs from neutralizing HIV-1.
Veterans Affairs New York Harbor Healthcare System - Manhattan Campus, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
Guomiao
G
Shen
Veterans Affairs New York Harbor Healthcare System - Manhattan Campus, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
Chitra
C
Upadhyay
Veterans Affairs New York Harbor Healthcare System - Manhattan Campus, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
Jing
J
Zhang
Department of Biochemistry and Pharmacology, New York University School of Medicine, New York, New York, United States of America.
Ruimin
R
Pan
Veterans Affairs New York Harbor Healthcare System - Manhattan Campus, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
Susan
S
Zolla-Pazner
Department of Biochemistry and Pharmacology, New York University School of Medicine, New York, New York, United States of America.
Xiang-Peng
XP
Kong
Veterans Affairs New York Harbor Healthcare System - Manhattan Campus, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
Catarina E
CE
Hioe
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120