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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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CAP257 broadly neutralizing antibodies develop sequentially in three distinct waves.A) Longitudinal neutralization of the autologous CAP257 virus (black) and 37 heterologous viruses neutralized by CAP257 plasma at titers >1∶100. The ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). Three peaks in heterologous neutralization titers at 67, 122, and 213 weeks p.i. are indicated with dotted lines. Heterologous viruses are colored according to subtype (A = green, B = blue, C = red). B) A summary of the three waves of heterologous neutralization defined by a representative virus, superimposed over the neutralization kinetics shown in Figure 1A. Wave 1 was subtype C specific and is colored red. Wave 2 neutralized viruses from all three clades and is colored green. Wave 3 is colored brown. C) Adsorption of heterologous neutralization at the peak of each of the three waves. Percentage inhibition (y-axis) is shown versus plasma dilution (x-axis). Untreated plasma is shown in black, blank beads in grey and beads coated with recombinant proteins are shown in red (wave 1), blue/green (wave 2) or brown (wave 3).
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ppat-1003738-g001: CAP257 broadly neutralizing antibodies develop sequentially in three distinct waves.A) Longitudinal neutralization of the autologous CAP257 virus (black) and 37 heterologous viruses neutralized by CAP257 plasma at titers >1∶100. The ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). Three peaks in heterologous neutralization titers at 67, 122, and 213 weeks p.i. are indicated with dotted lines. Heterologous viruses are colored according to subtype (A = green, B = blue, C = red). B) A summary of the three waves of heterologous neutralization defined by a representative virus, superimposed over the neutralization kinetics shown in Figure 1A. Wave 1 was subtype C specific and is colored red. Wave 2 neutralized viruses from all three clades and is colored green. Wave 3 is colored brown. C) Adsorption of heterologous neutralization at the peak of each of the three waves. Percentage inhibition (y-axis) is shown versus plasma dilution (x-axis). Untreated plasma is shown in black, blank beads in grey and beads coated with recombinant proteins are shown in red (wave 1), blue/green (wave 2) or brown (wave 3).

Mentions: We have previously described the development of neutralization breadth in CAP257 using longitudinal plasma samples from HIV-1 seroconversion to three years post-infection (p.i.) [7]. Here, we extended this analysis until the start of anti-retroviral therapy at four and a half years p.i. (Figure 1A). Longitudinal plasma was tested against the autologous CAP257 virus amplified from the earliest available time point (7 weeks p.i.), the subtype C consensus sequence (ConC) [33], 4 Tier 1b viruses, and 39 Tier 2 viruses [34]. Autologous neutralizing antibodies appeared by 14 weeks of infection with a peak titer at two years of 1∶6,754. This was followed by the neutralization of heterologous viruses 30 weeks after infection. CAP257 neutralized 84% of the heterologous viruses at three years (174 weeks) with neutralization breadth of 100% against subtype A (6/6 viruses), 96% against subtype C (25/26 viruses, including ConC), and 50% against subtype B (6/12 viruses). The titers of these broadly neutralizing antibodies peaked and waned in three separate waves.


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)

CAP257 broadly neutralizing antibodies develop sequentially in three distinct waves.A) Longitudinal neutralization of the autologous CAP257 virus (black) and 37 heterologous viruses neutralized by CAP257 plasma at titers >1∶100. The ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). Three peaks in heterologous neutralization titers at 67, 122, and 213 weeks p.i. are indicated with dotted lines. Heterologous viruses are colored according to subtype (A = green, B = blue, C = red). B) A summary of the three waves of heterologous neutralization defined by a representative virus, superimposed over the neutralization kinetics shown in Figure 1A. Wave 1 was subtype C specific and is colored red. Wave 2 neutralized viruses from all three clades and is colored green. Wave 3 is colored brown. C) Adsorption of heterologous neutralization at the peak of each of the three waves. Percentage inhibition (y-axis) is shown versus plasma dilution (x-axis). Untreated plasma is shown in black, blank beads in grey and beads coated with recombinant proteins are shown in red (wave 1), blue/green (wave 2) or brown (wave 3).
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1003738-g001: CAP257 broadly neutralizing antibodies develop sequentially in three distinct waves.A) Longitudinal neutralization of the autologous CAP257 virus (black) and 37 heterologous viruses neutralized by CAP257 plasma at titers >1∶100. The ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). Three peaks in heterologous neutralization titers at 67, 122, and 213 weeks p.i. are indicated with dotted lines. Heterologous viruses are colored according to subtype (A = green, B = blue, C = red). B) A summary of the three waves of heterologous neutralization defined by a representative virus, superimposed over the neutralization kinetics shown in Figure 1A. Wave 1 was subtype C specific and is colored red. Wave 2 neutralized viruses from all three clades and is colored green. Wave 3 is colored brown. C) Adsorption of heterologous neutralization at the peak of each of the three waves. Percentage inhibition (y-axis) is shown versus plasma dilution (x-axis). Untreated plasma is shown in black, blank beads in grey and beads coated with recombinant proteins are shown in red (wave 1), blue/green (wave 2) or brown (wave 3).
Mentions: We have previously described the development of neutralization breadth in CAP257 using longitudinal plasma samples from HIV-1 seroconversion to three years post-infection (p.i.) [7]. Here, we extended this analysis until the start of anti-retroviral therapy at four and a half years p.i. (Figure 1A). Longitudinal plasma was tested against the autologous CAP257 virus amplified from the earliest available time point (7 weeks p.i.), the subtype C consensus sequence (ConC) [33], 4 Tier 1b viruses, and 39 Tier 2 viruses [34]. Autologous neutralizing antibodies appeared by 14 weeks of infection with a peak titer at two years of 1∶6,754. This was followed by the neutralization of heterologous viruses 30 weeks after infection. CAP257 neutralized 84% of the heterologous viruses at three years (174 weeks) with neutralization breadth of 100% against subtype A (6/6 viruses), 96% against subtype C (25/26 viruses, including ConC), and 50% against subtype B (6/12 viruses). The titers of these broadly neutralizing antibodies peaked and waned in three separate waves.

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