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Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes.

Wibmer CK, Bhiman JN, Gray ES, Tumba N, Abdool Karim SS, Williamson C, Morris L, Moore PL - PLoS Pathog. (2013)

Bottom Line: Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276.Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site.The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined.

View Article: PubMed Central - PubMed

Affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), of the National Health Laboratory Service (NHLS), Johannesburg, South Africa ; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

ABSTRACT
Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.

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The R456 side chain stabilizes the CD4bs epitope through hydrogen bonding.A diagram of the 93TH057 gp120 crystal structure (pdb file 4JKP) shown in an orientation similar to the angle of approach for CD4. The crystalized part of the N276 attached glycan (GlcNAc2Man4) is shown with purple spheres. The D-loop is shown in green, the V5 loop is shown in cyan, and the R456 residue is shown in pink. Oxygen atoms are colored red, and nitrogen atoms blue. The inset shows a magnified view of the interaction between R456 and residues in the D-loop or the β24 strand. Putative hydrogen bonds are shown with dotted orange lines. The image was created using The PyMOL Molecular Graphics System, Version 1.3r1edu, Schrödinger LLC.
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ppat-1003738-g011: The R456 side chain stabilizes the CD4bs epitope through hydrogen bonding.A diagram of the 93TH057 gp120 crystal structure (pdb file 4JKP) shown in an orientation similar to the angle of approach for CD4. The crystalized part of the N276 attached glycan (GlcNAc2Man4) is shown with purple spheres. The D-loop is shown in green, the V5 loop is shown in cyan, and the R456 residue is shown in pink. Oxygen atoms are colored red, and nitrogen atoms blue. The inset shows a magnified view of the interaction between R456 and residues in the D-loop or the β24 strand. Putative hydrogen bonds are shown with dotted orange lines. The image was created using The PyMOL Molecular Graphics System, Version 1.3r1edu, Schrödinger LLC.

Mentions: Characterization of viral escape from CAP257 CD4bs antibodies indicated that deletion of the N276 glycan alone did not confer complete resistance. Escape required accumulating mutations in the CD4bs site, consistent with the functional conservation of this epitope. In addition to deletion of the N276 glycan, CAP257 escape occurred through a R456W mutation that also significantly affected neutralization by VRC01 (30 fold) and HJ16 (514 fold). This mutation likely contributed towards the evolution of VRC01 resistant virus by 174 weeks. W456 is extremely rare, occurring in only 0.78% (27 of 3,481) of sequences in the LANL HIV-1 sequence database. A crystal complex for HJ16 is not available, however the structure of VRC01 bound to its epitope showed that this antibody does not make significant contact with the R456 side chain in gp120, but rather hydrogen bonds with the R456 backbone carbonyl group. This suggests that the R456W mutation provides an indirect mechanism for resistance. The highly conserved R456 side chain can make hydrogen bonds with backbone carbonyl groups of amino acids at position 277 and 278 in the D-loop, as well as hydrogen bonds with E466 side chain in β24, C-terminal to V5 (Figure 11). Loss of these bonds and localized conformational changes to accommodate a bulky tryptophan residue may destabilize this critical component of the CD4bs epitope [52], [56], [71].


Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes.

Wibmer CK, Bhiman JN, Gray ES, Tumba N, Abdool Karim SS, Williamson C, Morris L, Moore PL - PLoS Pathog. (2013)

The R456 side chain stabilizes the CD4bs epitope through hydrogen bonding.A diagram of the 93TH057 gp120 crystal structure (pdb file 4JKP) shown in an orientation similar to the angle of approach for CD4. The crystalized part of the N276 attached glycan (GlcNAc2Man4) is shown with purple spheres. The D-loop is shown in green, the V5 loop is shown in cyan, and the R456 residue is shown in pink. Oxygen atoms are colored red, and nitrogen atoms blue. The inset shows a magnified view of the interaction between R456 and residues in the D-loop or the β24 strand. Putative hydrogen bonds are shown with dotted orange lines. The image was created using The PyMOL Molecular Graphics System, Version 1.3r1edu, Schrödinger LLC.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814426&req=5

ppat-1003738-g011: The R456 side chain stabilizes the CD4bs epitope through hydrogen bonding.A diagram of the 93TH057 gp120 crystal structure (pdb file 4JKP) shown in an orientation similar to the angle of approach for CD4. The crystalized part of the N276 attached glycan (GlcNAc2Man4) is shown with purple spheres. The D-loop is shown in green, the V5 loop is shown in cyan, and the R456 residue is shown in pink. Oxygen atoms are colored red, and nitrogen atoms blue. The inset shows a magnified view of the interaction between R456 and residues in the D-loop or the β24 strand. Putative hydrogen bonds are shown with dotted orange lines. The image was created using The PyMOL Molecular Graphics System, Version 1.3r1edu, Schrödinger LLC.
Mentions: Characterization of viral escape from CAP257 CD4bs antibodies indicated that deletion of the N276 glycan alone did not confer complete resistance. Escape required accumulating mutations in the CD4bs site, consistent with the functional conservation of this epitope. In addition to deletion of the N276 glycan, CAP257 escape occurred through a R456W mutation that also significantly affected neutralization by VRC01 (30 fold) and HJ16 (514 fold). This mutation likely contributed towards the evolution of VRC01 resistant virus by 174 weeks. W456 is extremely rare, occurring in only 0.78% (27 of 3,481) of sequences in the LANL HIV-1 sequence database. A crystal complex for HJ16 is not available, however the structure of VRC01 bound to its epitope showed that this antibody does not make significant contact with the R456 side chain in gp120, but rather hydrogen bonds with the R456 backbone carbonyl group. This suggests that the R456W mutation provides an indirect mechanism for resistance. The highly conserved R456 side chain can make hydrogen bonds with backbone carbonyl groups of amino acids at position 277 and 278 in the D-loop, as well as hydrogen bonds with E466 side chain in β24, C-terminal to V5 (Figure 11). Loss of these bonds and localized conformational changes to accommodate a bulky tryptophan residue may destabilize this critical component of the CD4bs epitope [52], [56], [71].

Bottom Line: Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276.Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site.The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined.

View Article: PubMed Central - PubMed

Affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), of the National Health Laboratory Service (NHLS), Johannesburg, South Africa ; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

ABSTRACT
Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.

Show MeSH
Related in: MedlinePlus