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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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Maturation of the wave 2 CD4bs response results in the increased neutralization breadth of CAP257 plasma.A) Summary of early (green) and late (blue) heterologous neutralization by wave 2 antibodies superimposed over the individual virus neutralization kinetics (grey). Viruses neutralized by V2 antibodies in wave 1 have been excluded. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) Amino acid sequence alignment of heterologous viruses depicted in (A). The timing of early or late heterologous neutralization is shown on the left with horizontal lines. The N276 glycan is shaded grey, and position 279 is boxed in orange. The frequency of the N279D mutation or disrupted N276 glycosylation within the two groups is shown with orange or purple pie slices respectively. The N-terminal region of the D-loop is boxed in blue.
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ppat-1003738-g007: Maturation of the wave 2 CD4bs response results in the increased neutralization breadth of CAP257 plasma.A) Summary of early (green) and late (blue) heterologous neutralization by wave 2 antibodies superimposed over the individual virus neutralization kinetics (grey). Viruses neutralized by V2 antibodies in wave 1 have been excluded. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) Amino acid sequence alignment of heterologous viruses depicted in (A). The timing of early or late heterologous neutralization is shown on the left with horizontal lines. The N276 glycan is shaded grey, and position 279 is boxed in orange. The frequency of the N279D mutation or disrupted N276 glycosylation within the two groups is shown with orange or purple pie slices respectively. The N-terminal region of the D-loop is boxed in blue.

Mentions: These data are consistent with accumulating resistance to wave 2, and suggest that after each successive round of escape, new antibody variants emerged that were able to neutralize first the N279D mutant, and then later autologous viruses with additional polymorphisms at positions 276, 278, or 456. We wished to determine whether the ability to neutralize escaped viral variants correlated with increased wave 2 neutralization breadth. Heterologous viruses neutralized by wave 2 were divided into two groups, those neutralized at 67 weeks p.i. (early wave 2 neutralization), and those first neutralized at 93 weeks p.i. (late wave 2 neutralization) after the emergence of initial wave 2 escape mutations (Figure 7A). Viruses also neutralized by wave 1 were omitted as the overlapping titers confounded this analysis. Inspection of the envelope sequences (particularly in the D-loop) showed that all of the viruses neutralized by early wave 2 antibodies had the N279 immunotype (Figure 7B – boxed in orange). In contrast 44% of viruses neutralized by later wave 2 antibodies had the D279 immunotype. Furthermore, of the viruses neutralized by later wave 2 antibodies, one (Q259) lacked the N276 glycan and four others also had additional non-conservative mutations at positions 273–275 in the N-terminus of the D-loop (Figure 7B – boxed in blue) that may also affect early wave 2 neutralization. These data suggest that wave 2 escape mutations guided maturation of the CD4bs response, enabling later wave 2 antibodies to neutralize additional heterologous viruses and ultimately resulting in the increased neutralization breadth of CAP257 plasma.


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)

Maturation of the wave 2 CD4bs response results in the increased neutralization breadth of CAP257 plasma.A) Summary of early (green) and late (blue) heterologous neutralization by wave 2 antibodies superimposed over the individual virus neutralization kinetics (grey). Viruses neutralized by V2 antibodies in wave 1 have been excluded. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) Amino acid sequence alignment of heterologous viruses depicted in (A). The timing of early or late heterologous neutralization is shown on the left with horizontal lines. The N276 glycan is shaded grey, and position 279 is boxed in orange. The frequency of the N279D mutation or disrupted N276 glycosylation within the two groups is shown with orange or purple pie slices respectively. The N-terminal region of the D-loop is boxed in blue.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1003738-g007: Maturation of the wave 2 CD4bs response results in the increased neutralization breadth of CAP257 plasma.A) Summary of early (green) and late (blue) heterologous neutralization by wave 2 antibodies superimposed over the individual virus neutralization kinetics (grey). Viruses neutralized by V2 antibodies in wave 1 have been excluded. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) Amino acid sequence alignment of heterologous viruses depicted in (A). The timing of early or late heterologous neutralization is shown on the left with horizontal lines. The N276 glycan is shaded grey, and position 279 is boxed in orange. The frequency of the N279D mutation or disrupted N276 glycosylation within the two groups is shown with orange or purple pie slices respectively. The N-terminal region of the D-loop is boxed in blue.
Mentions: These data are consistent with accumulating resistance to wave 2, and suggest that after each successive round of escape, new antibody variants emerged that were able to neutralize first the N279D mutant, and then later autologous viruses with additional polymorphisms at positions 276, 278, or 456. We wished to determine whether the ability to neutralize escaped viral variants correlated with increased wave 2 neutralization breadth. Heterologous viruses neutralized by wave 2 were divided into two groups, those neutralized at 67 weeks p.i. (early wave 2 neutralization), and those first neutralized at 93 weeks p.i. (late wave 2 neutralization) after the emergence of initial wave 2 escape mutations (Figure 7A). Viruses also neutralized by wave 1 were omitted as the overlapping titers confounded this analysis. Inspection of the envelope sequences (particularly in the D-loop) showed that all of the viruses neutralized by early wave 2 antibodies had the N279 immunotype (Figure 7B – boxed in orange). In contrast 44% of viruses neutralized by later wave 2 antibodies had the D279 immunotype. Furthermore, of the viruses neutralized by later wave 2 antibodies, one (Q259) lacked the N276 glycan and four others also had additional non-conservative mutations at positions 273–275 in the N-terminus of the D-loop (Figure 7B – boxed in blue) that may also affect early wave 2 neutralization. These data suggest that wave 2 escape mutations guided maturation of the CD4bs response, enabling later wave 2 antibodies to neutralize additional heterologous viruses and ultimately resulting in the increased neutralization breadth of CAP257 plasma.

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