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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 first wave of broadly neutralizing antibodies targets residues in the V2 region.A) Longitudinal neutralization of ConC V2 mutants. ConC wild-type (wt) is shown in red. V2 mutants F159A, N160A, R166A, K168A, K169E, K171A, and I181A that abrogated wave 1 neutralization are shown in purple. The D167N mutation that enhanced wave 1 neutralization is shown in orange, while the L165A mutation that resulted in universal neutralization sensitivity is shown in grey. The timing of wave 1 (red), wave 2 (green), and wave 3 (brown) neutralization is summarized above as horizontal lines, while the peak titers at each wave are indicated with dotted lines. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) The dependence of CAP257 wave 1 neutralizing antibodies (at 67 weeks p.i.) on V2 residues in ConC, compared to monoclonal antibodies PGT145, CH01-04, and PG9/16. Complete abrogation of neutralization is colored red, 2–10 fold reductions in IC50 are colored yellow, and >10 fold reductions in IC50 are colored orange.
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ppat-1003738-g002: The first wave of broadly neutralizing antibodies targets residues in the V2 region.A) Longitudinal neutralization of ConC V2 mutants. ConC wild-type (wt) is shown in red. V2 mutants F159A, N160A, R166A, K168A, K169E, K171A, and I181A that abrogated wave 1 neutralization are shown in purple. The D167N mutation that enhanced wave 1 neutralization is shown in orange, while the L165A mutation that resulted in universal neutralization sensitivity is shown in grey. The timing of wave 1 (red), wave 2 (green), and wave 3 (brown) neutralization is summarized above as horizontal lines, while the peak titers at each wave are indicated with dotted lines. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) The dependence of CAP257 wave 1 neutralizing antibodies (at 67 weeks p.i.) on V2 residues in ConC, compared to monoclonal antibodies PGT145, CH01-04, and PG9/16. Complete abrogation of neutralization is colored red, 2–10 fold reductions in IC50 are colored yellow, and >10 fold reductions in IC50 are colored orange.

Mentions: The inability of gp120 to adsorb out wave 1 neutralization suggested these antibodies might recognize the trimer specific epitope in V1/V2 defined by PG9/16 [16]. Therefore, we performed mapping studies using ConC, which was neutralized by all three waves of neutralizing antibodies (Figure 2A – red curve). Seven mutations in the V2 region (F159A, N160A, R166A, K168A, K169E, K171A, and I181A) each abrogated wave 1 neutralization, but did not significantly affect the titers of waves 2 or 3 (Figure 2A – purple curves). In contrast, a D167N mutation resulted in enhanced neutralization by wave 1 antibodies, but did not significantly affect the titers of waves 2 or 3 (Figure 2A – orange curve). A second mutation (L165A) also resulted in significant neutralization enhancement at all the time points tested, including those preceding breadth (Figure 2A – grey curve), suggesting that this mutation resulted in general neutralization sensitivity. Overall, these data indicated that wave 1 antibodies (but not waves 2 or 3) targeted residues in the V2 region.


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 first wave of broadly neutralizing antibodies targets residues in the V2 region.A) Longitudinal neutralization of ConC V2 mutants. ConC wild-type (wt) is shown in red. V2 mutants F159A, N160A, R166A, K168A, K169E, K171A, and I181A that abrogated wave 1 neutralization are shown in purple. The D167N mutation that enhanced wave 1 neutralization is shown in orange, while the L165A mutation that resulted in universal neutralization sensitivity is shown in grey. The timing of wave 1 (red), wave 2 (green), and wave 3 (brown) neutralization is summarized above as horizontal lines, while the peak titers at each wave are indicated with dotted lines. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) The dependence of CAP257 wave 1 neutralizing antibodies (at 67 weeks p.i.) on V2 residues in ConC, compared to monoclonal antibodies PGT145, CH01-04, and PG9/16. Complete abrogation of neutralization is colored red, 2–10 fold reductions in IC50 are colored yellow, and >10 fold reductions in IC50 are colored orange.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1003738-g002: The first wave of broadly neutralizing antibodies targets residues in the V2 region.A) Longitudinal neutralization of ConC V2 mutants. ConC wild-type (wt) is shown in red. V2 mutants F159A, N160A, R166A, K168A, K169E, K171A, and I181A that abrogated wave 1 neutralization are shown in purple. The D167N mutation that enhanced wave 1 neutralization is shown in orange, while the L165A mutation that resulted in universal neutralization sensitivity is shown in grey. The timing of wave 1 (red), wave 2 (green), and wave 3 (brown) neutralization is summarized above as horizontal lines, while the peak titers at each wave are indicated with dotted lines. ID50 titers (y-axis) are shown versus weeks p.i. (x-axis). B) The dependence of CAP257 wave 1 neutralizing antibodies (at 67 weeks p.i.) on V2 residues in ConC, compared to monoclonal antibodies PGT145, CH01-04, and PG9/16. Complete abrogation of neutralization is colored red, 2–10 fold reductions in IC50 are colored yellow, and >10 fold reductions in IC50 are colored orange.
Mentions: The inability of gp120 to adsorb out wave 1 neutralization suggested these antibodies might recognize the trimer specific epitope in V1/V2 defined by PG9/16 [16]. Therefore, we performed mapping studies using ConC, which was neutralized by all three waves of neutralizing antibodies (Figure 2A – red curve). Seven mutations in the V2 region (F159A, N160A, R166A, K168A, K169E, K171A, and I181A) each abrogated wave 1 neutralization, but did not significantly affect the titers of waves 2 or 3 (Figure 2A – purple curves). In contrast, a D167N mutation resulted in enhanced neutralization by wave 1 antibodies, but did not significantly affect the titers of waves 2 or 3 (Figure 2A – orange curve). A second mutation (L165A) also resulted in significant neutralization enhancement at all the time points tested, including those preceding breadth (Figure 2A – grey curve), suggesting that this mutation resulted in general neutralization sensitivity. Overall, these data indicated that wave 1 antibodies (but not waves 2 or 3) targeted residues in the V2 region.

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