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Viral escape from neutralizing antibodies in early subtype A HIV-1 infection drives an increase in autologous neutralization breadth.

Murphy MK, Yue L, Pan R, Boliar S, Sethi A, Tian J, Pfafferot K, Karita E, Allen SA, Cormier E, Goepfert PA, Borrow P, Robinson JE, Gnanakaran S, Hunter E, Kong XP, Derdeyn CA - PLoS Pathog. (2013)

Bottom Line: Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions.Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env.This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT
Antibodies that neutralize (nAbs) genetically diverse HIV-1 strains have been recovered from a subset of HIV-1 infected subjects during chronic infection. Exact mechanisms that expand the otherwise narrow neutralization capacity observed during early infection are, however, currently undefined. Here we characterized the earliest nAb responses in a subtype A HIV-1 infected Rwandan seroconverter who later developed moderate cross-clade nAb breadth, using (i) envelope (Env) glycoproteins from the transmitted/founder virus and twenty longitudinal nAb escape variants, (ii) longitudinal autologous plasma, and (iii) autologous monoclonal antibodies (mAbs). Initially, nAbs targeted a single region of gp120, which flanked the V3 domain and involved the alpha2 helix. A single amino acid change at one of three positions in this region conferred early escape. One immunoglobulin heavy chain and two light chains recovered from autologous B cells comprised two mAbs, 19.3H-L1 and 19.3H-L3, which neutralized the founder Env along with one or three of the early escape variants carrying these mutations, respectively. Neither mAb neutralized later nAb escape or heterologous Envs. Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions. Resistance to mAb neutralization arose in later Envs through alteration of two glycans spatially adjacent to the initial escape signatures. The cross-neutralizing nAbs that ultimately developed failed to target any of the defined V3-proximal changes generated during the first year of infection in this subject. Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env. This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.

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Homology model of R880F gp120.A 3-dimensional gp120 monomer (blue) based on the R880F transmitted/founder Env 0-A6/B24 sequence was homology modeled from existing gp120 structures (see Materials and Methods) and spatially oriented using MacPyMOL software to illuminate the region targeted by the earliest nAbs in this subject. Functional domains such as the alpha2 helix (green) and V3 (magenta) are delineated, and subject-specific amino acid numbering indicates positions that mutated at 2-months post-seroconversion to confer nAb escape. These residues (295, 338, and 341 in red) nest together in a putative epitope.
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ppat-1003173-g004: Homology model of R880F gp120.A 3-dimensional gp120 monomer (blue) based on the R880F transmitted/founder Env 0-A6/B24 sequence was homology modeled from existing gp120 structures (see Materials and Methods) and spatially oriented using MacPyMOL software to illuminate the region targeted by the earliest nAbs in this subject. Functional domains such as the alpha2 helix (green) and V3 (magenta) are delineated, and subject-specific amino acid numbering indicates positions that mutated at 2-months post-seroconversion to confer nAb escape. These residues (295, 338, and 341 in red) nest together in a putative epitope.

Mentions: Though positions 295, 338, and 341 appear disparate in the linear gp120 sequence, these residues cluster when plotted onto a 3-dimensional representation of the R880F founder Env sequence, which was modeled using all existing structures for CD4-bound HIV-1 gp120 (Figure 4). This proposed epitope emerges near the base of the V3 domain, which is well exposed on the native trimer and is also targeted by the broadly neutralizing, glycan-dependent mAb PGT128 [8]. The spatial proximity of these three residues provides evidence for a single nAb epitope during early subtype A HIV-1 infection and an explanation for why a substitution at any one of the three positions independently caused nAb resistance.


Viral escape from neutralizing antibodies in early subtype A HIV-1 infection drives an increase in autologous neutralization breadth.

Murphy MK, Yue L, Pan R, Boliar S, Sethi A, Tian J, Pfafferot K, Karita E, Allen SA, Cormier E, Goepfert PA, Borrow P, Robinson JE, Gnanakaran S, Hunter E, Kong XP, Derdeyn CA - PLoS Pathog. (2013)

Homology model of R880F gp120.A 3-dimensional gp120 monomer (blue) based on the R880F transmitted/founder Env 0-A6/B24 sequence was homology modeled from existing gp120 structures (see Materials and Methods) and spatially oriented using MacPyMOL software to illuminate the region targeted by the earliest nAbs in this subject. Functional domains such as the alpha2 helix (green) and V3 (magenta) are delineated, and subject-specific amino acid numbering indicates positions that mutated at 2-months post-seroconversion to confer nAb escape. These residues (295, 338, and 341 in red) nest together in a putative epitope.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585129&req=5

ppat-1003173-g004: Homology model of R880F gp120.A 3-dimensional gp120 monomer (blue) based on the R880F transmitted/founder Env 0-A6/B24 sequence was homology modeled from existing gp120 structures (see Materials and Methods) and spatially oriented using MacPyMOL software to illuminate the region targeted by the earliest nAbs in this subject. Functional domains such as the alpha2 helix (green) and V3 (magenta) are delineated, and subject-specific amino acid numbering indicates positions that mutated at 2-months post-seroconversion to confer nAb escape. These residues (295, 338, and 341 in red) nest together in a putative epitope.
Mentions: Though positions 295, 338, and 341 appear disparate in the linear gp120 sequence, these residues cluster when plotted onto a 3-dimensional representation of the R880F founder Env sequence, which was modeled using all existing structures for CD4-bound HIV-1 gp120 (Figure 4). This proposed epitope emerges near the base of the V3 domain, which is well exposed on the native trimer and is also targeted by the broadly neutralizing, glycan-dependent mAb PGT128 [8]. The spatial proximity of these three residues provides evidence for a single nAb epitope during early subtype A HIV-1 infection and an explanation for why a substitution at any one of the three positions independently caused nAb resistance.

Bottom Line: Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions.Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env.This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, Georgia, United States of America.

ABSTRACT
Antibodies that neutralize (nAbs) genetically diverse HIV-1 strains have been recovered from a subset of HIV-1 infected subjects during chronic infection. Exact mechanisms that expand the otherwise narrow neutralization capacity observed during early infection are, however, currently undefined. Here we characterized the earliest nAb responses in a subtype A HIV-1 infected Rwandan seroconverter who later developed moderate cross-clade nAb breadth, using (i) envelope (Env) glycoproteins from the transmitted/founder virus and twenty longitudinal nAb escape variants, (ii) longitudinal autologous plasma, and (iii) autologous monoclonal antibodies (mAbs). Initially, nAbs targeted a single region of gp120, which flanked the V3 domain and involved the alpha2 helix. A single amino acid change at one of three positions in this region conferred early escape. One immunoglobulin heavy chain and two light chains recovered from autologous B cells comprised two mAbs, 19.3H-L1 and 19.3H-L3, which neutralized the founder Env along with one or three of the early escape variants carrying these mutations, respectively. Neither mAb neutralized later nAb escape or heterologous Envs. Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions. Resistance to mAb neutralization arose in later Envs through alteration of two glycans spatially adjacent to the initial escape signatures. The cross-neutralizing nAbs that ultimately developed failed to target any of the defined V3-proximal changes generated during the first year of infection in this subject. Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env. This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.

Show MeSH
Related in: MedlinePlus