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Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.

Wagh K, Bhattacharya T, Williamson C, Robles A, Bayne M, Garrity J, Rist M, Rademeyer C, Yoon H, Lapedes A, Gao H, Greene K, Louder MK, Kong R, Karim SA, Burton DR, Barouch DH, Nussenzweig MC, Mascola JR, Morris L, Montefiori DC, Korber B, Seaman MS - PLoS Pathog. (2016)

Bottom Line: While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit.Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations.By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.

ABSTRACT
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

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Comparison of best-in-category bnAb combinations for potency and breadth of neutralization.Comparisons of best combinations from each category within the 2- (A-C), 3- (D-F) and 4- (G-I) bnAb combinations are presented. Shown below each combination are its geometric mean and median IC80 titer and the percent viral coverage at IC80 < 10 μg/ml (A, D, G). Combinations are ordered using geometric mean IC80 titers, and a combination is indicated as better than (‘>‘) the proceeding combination when the difference in geometric mean IC80 exceeded 0.001 μg/ml, otherwise it is indicated as similar (‘~’). The distributions of IC80 scores for the best combinations were compared using a Wilcoxon Rank Sum Test, and only those p-values with q-value < 0.1 are shown. Potency-breadth curves (B, E, H) and distributions of IC80 values (C, F, I) for the top 2 combinations are shown. Grey lines in C, F, I connect the predicted IC80 values for the same virus.
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ppat.1005520.g004: Comparison of best-in-category bnAb combinations for potency and breadth of neutralization.Comparisons of best combinations from each category within the 2- (A-C), 3- (D-F) and 4- (G-I) bnAb combinations are presented. Shown below each combination are its geometric mean and median IC80 titer and the percent viral coverage at IC80 < 10 μg/ml (A, D, G). Combinations are ordered using geometric mean IC80 titers, and a combination is indicated as better than (‘>‘) the proceeding combination when the difference in geometric mean IC80 exceeded 0.001 μg/ml, otherwise it is indicated as similar (‘~’). The distributions of IC80 scores for the best combinations were compared using a Wilcoxon Rank Sum Test, and only those p-values with q-value < 0.1 are shown. Potency-breadth curves (B, E, H) and distributions of IC80 values (C, F, I) for the top 2 combinations are shown. Grey lines in C, F, I connect the predicted IC80 values for the same virus.

Mentions: The combinations were stratified by the number of bnAbs targeting different epitopes (referred to as “categories”, e.g., CD4bs+V2g is a combination of a CD4bs and a V2-glycan bnAb, and V2g(2x)+V3g has two V2-glycan and one V3-glycan bnAbs). Within each category, multiple combinations were possible due to multiple bnAbs targeting the same epitope. Best-in-category bnAb combinations were identified as those with the lowest geometric mean IC80 values for the 200 viruses (highlighted in Fig 3 by dark, bold lines). Of note, the area under the IC80 potency-breadth curve is negatively, but linearly, and almost perfectly correlated to the Log10 geometric mean IC80. Thus using either measure gives identical results. The best-in-category combinations were not always clear, as second best combinations were very comparable (e.g. CAP256-VRC26.25 + 10-1074V + PGT128 or PGT121 with geometric mean IC80 of 0.007 and 0.0071μg/ml, respectively). Comparisons of best-in-category combinations having the same number of bnAbs are shown in Fig 4.


Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.

Wagh K, Bhattacharya T, Williamson C, Robles A, Bayne M, Garrity J, Rist M, Rademeyer C, Yoon H, Lapedes A, Gao H, Greene K, Louder MK, Kong R, Karim SA, Burton DR, Barouch DH, Nussenzweig MC, Mascola JR, Morris L, Montefiori DC, Korber B, Seaman MS - PLoS Pathog. (2016)

Comparison of best-in-category bnAb combinations for potency and breadth of neutralization.Comparisons of best combinations from each category within the 2- (A-C), 3- (D-F) and 4- (G-I) bnAb combinations are presented. Shown below each combination are its geometric mean and median IC80 titer and the percent viral coverage at IC80 < 10 μg/ml (A, D, G). Combinations are ordered using geometric mean IC80 titers, and a combination is indicated as better than (‘>‘) the proceeding combination when the difference in geometric mean IC80 exceeded 0.001 μg/ml, otherwise it is indicated as similar (‘~’). The distributions of IC80 scores for the best combinations were compared using a Wilcoxon Rank Sum Test, and only those p-values with q-value < 0.1 are shown. Potency-breadth curves (B, E, H) and distributions of IC80 values (C, F, I) for the top 2 combinations are shown. Grey lines in C, F, I connect the predicted IC80 values for the same virus.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4814126&req=5

ppat.1005520.g004: Comparison of best-in-category bnAb combinations for potency and breadth of neutralization.Comparisons of best combinations from each category within the 2- (A-C), 3- (D-F) and 4- (G-I) bnAb combinations are presented. Shown below each combination are its geometric mean and median IC80 titer and the percent viral coverage at IC80 < 10 μg/ml (A, D, G). Combinations are ordered using geometric mean IC80 titers, and a combination is indicated as better than (‘>‘) the proceeding combination when the difference in geometric mean IC80 exceeded 0.001 μg/ml, otherwise it is indicated as similar (‘~’). The distributions of IC80 scores for the best combinations were compared using a Wilcoxon Rank Sum Test, and only those p-values with q-value < 0.1 are shown. Potency-breadth curves (B, E, H) and distributions of IC80 values (C, F, I) for the top 2 combinations are shown. Grey lines in C, F, I connect the predicted IC80 values for the same virus.
Mentions: The combinations were stratified by the number of bnAbs targeting different epitopes (referred to as “categories”, e.g., CD4bs+V2g is a combination of a CD4bs and a V2-glycan bnAb, and V2g(2x)+V3g has two V2-glycan and one V3-glycan bnAbs). Within each category, multiple combinations were possible due to multiple bnAbs targeting the same epitope. Best-in-category bnAb combinations were identified as those with the lowest geometric mean IC80 values for the 200 viruses (highlighted in Fig 3 by dark, bold lines). Of note, the area under the IC80 potency-breadth curve is negatively, but linearly, and almost perfectly correlated to the Log10 geometric mean IC80. Thus using either measure gives identical results. The best-in-category combinations were not always clear, as second best combinations were very comparable (e.g. CAP256-VRC26.25 + 10-1074V + PGT128 or PGT121 with geometric mean IC80 of 0.007 and 0.0071μg/ml, respectively). Comparisons of best-in-category combinations having the same number of bnAbs are shown in Fig 4.

Bottom Line: While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit.Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations.By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.

ABSTRACT
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

Show MeSH
Related in: MedlinePlus