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Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent.

Reh L, Magnus C, Schanz M, Weber J, Uhr T, Rusert P, Trkola A - PLoS Pathog. (2015)

Bottom Line: Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection.Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs.Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Virology, University of Zürich, Zürich, Switzerland.

ABSTRACT
An increasing number of broadly neutralizing antibodies (bnAbs) are considered leads for HIV-1 vaccine development and novel therapeutics. Here, we systematically explored the capacity of bnAbs to neutralize HIV-1 prior to and post-CD4 engagement and to block HIV-1 cell-cell transmission. Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection. Selection of bnAbs that are capable of suppressing HIV irrespective of the transmission mode therefore needs to be considered to ascertain their in vivo activity in therapeutic use and vaccines. Employing assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission to T cells, we probed a panel of 16 bnAbs for their activity against 11 viruses from subtypes A, B and C during both transmission modes. Over a wide range of bnAb-virus combinations tested, inhibitory activity against HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs. In rare bnAb-virus combinations, inhibition for both transmission modes was comparable but no bnAb potently blocked cell-cell transmission across all probed virus strains. Mathematical analysis indicated an increased probability of bnAb resistance mutations to arise in cell-cell rather than free virus spread, further highlighting the need to block this pathway. Importantly, the capacity to efficiently neutralize prior to CD4 engagement correlated with the inhibition efficacy against free virus but not cell-cell transmitted virus. Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner. In summary, bnAb activity against divergent viruses varied depending on the transmission mode and differed depending on the window of action during the entry process, underscoring that powerful combinations of bnAbs are needed for in vivo application.

No MeSH data available.


Related in: MedlinePlus

Differential loss in cell-cell neutralization across bnAb classes.Interdependencies of inhibitory activity (IC50) against free and cell-cell transmitted virus (A) and the fold change in IC50 between free and cell-cell transmission (B) was determined for individual bnAb classes and all classes combined by Spearman correlation based on the untransformed data sets. R and p values are depicted. n.s. indicates a non-significant correlation. Data are derived from Fig 2, S5A–S5P Fig and S3 Table. Subtype A, B and C viruses are denoted in blue, black and orange, respectively.
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ppat.1004966.g003: Differential loss in cell-cell neutralization across bnAb classes.Interdependencies of inhibitory activity (IC50) against free and cell-cell transmitted virus (A) and the fold change in IC50 between free and cell-cell transmission (B) was determined for individual bnAb classes and all classes combined by Spearman correlation based on the untransformed data sets. R and p values are depicted. n.s. indicates a non-significant correlation. Data are derived from Fig 2, S5A–S5P Fig and S3 Table. Subtype A, B and C viruses are denoted in blue, black and orange, respectively.

Mentions: To determine if the reported losses in neutralization activity of cell-cell spread can be predicted by the bnAbs’ performance during free virus inhibition or if they need to be determined individually, we assessed the interdependence of potency in free virus and cell-cell neutralization and the extent of the activity loss inflicted by cell-cell transmission (Fig 3A and 3B). Inhibitory concentrations obtained for free virus and cell-cell neutralization proved to be linked (Fig 3A). Unexpectedly, efficacy in free virus inhibition and the extent of activity loss during cell-cell transmission showed an inverse correlation for V1V2- and V3-directed and to a lesser extent also for MPER-directed bnAbs, but not for bnAbs targeting the CD4bs (Fig 3B). Thus, with the exception of CD4bs-directed bnAbs, a higher loss in neutralization activity during cell-cell transmission was more frequently observed when bnAb activity against free virus transmission was very high, suggesting that features which steer the bnAbs’ ability to potently inhibit free virus spread are not equally decisive in cell-cell transmission. In fact, the opposite appeared to be true for some bnAb-virus combinations: The bnAbs that comparably neutralized a virus strain during both transmission modes were in most cases relatively weak inhibitors of these strains (2G12 for JR-FL and JR-CSF, PGT121 for REJO and BG505, PGT128 for BG505, PGT145 for ZM53, PG16 for DH123 and THRO, 10E8 for ZM53, 4E10 for JR-CSF and ZM53). High potency against free virus activity was only in two cases (PGT145 for BG505 and ZM109) paired with low loss of activity during cell-cell transmission (Fig 2B and 2D, S3 Table, S5J Fig). Collectively, this suggests that antibody features that steer high potency against free virus spread are not the driving factors determining the activity during cell-cell transmission.


Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent.

Reh L, Magnus C, Schanz M, Weber J, Uhr T, Rusert P, Trkola A - PLoS Pathog. (2015)

Differential loss in cell-cell neutralization across bnAb classes.Interdependencies of inhibitory activity (IC50) against free and cell-cell transmitted virus (A) and the fold change in IC50 between free and cell-cell transmission (B) was determined for individual bnAb classes and all classes combined by Spearman correlation based on the untransformed data sets. R and p values are depicted. n.s. indicates a non-significant correlation. Data are derived from Fig 2, S5A–S5P Fig and S3 Table. Subtype A, B and C viruses are denoted in blue, black and orange, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4497647&req=5

ppat.1004966.g003: Differential loss in cell-cell neutralization across bnAb classes.Interdependencies of inhibitory activity (IC50) against free and cell-cell transmitted virus (A) and the fold change in IC50 between free and cell-cell transmission (B) was determined for individual bnAb classes and all classes combined by Spearman correlation based on the untransformed data sets. R and p values are depicted. n.s. indicates a non-significant correlation. Data are derived from Fig 2, S5A–S5P Fig and S3 Table. Subtype A, B and C viruses are denoted in blue, black and orange, respectively.
Mentions: To determine if the reported losses in neutralization activity of cell-cell spread can be predicted by the bnAbs’ performance during free virus inhibition or if they need to be determined individually, we assessed the interdependence of potency in free virus and cell-cell neutralization and the extent of the activity loss inflicted by cell-cell transmission (Fig 3A and 3B). Inhibitory concentrations obtained for free virus and cell-cell neutralization proved to be linked (Fig 3A). Unexpectedly, efficacy in free virus inhibition and the extent of activity loss during cell-cell transmission showed an inverse correlation for V1V2- and V3-directed and to a lesser extent also for MPER-directed bnAbs, but not for bnAbs targeting the CD4bs (Fig 3B). Thus, with the exception of CD4bs-directed bnAbs, a higher loss in neutralization activity during cell-cell transmission was more frequently observed when bnAb activity against free virus transmission was very high, suggesting that features which steer the bnAbs’ ability to potently inhibit free virus spread are not equally decisive in cell-cell transmission. In fact, the opposite appeared to be true for some bnAb-virus combinations: The bnAbs that comparably neutralized a virus strain during both transmission modes were in most cases relatively weak inhibitors of these strains (2G12 for JR-FL and JR-CSF, PGT121 for REJO and BG505, PGT128 for BG505, PGT145 for ZM53, PG16 for DH123 and THRO, 10E8 for ZM53, 4E10 for JR-CSF and ZM53). High potency against free virus activity was only in two cases (PGT145 for BG505 and ZM109) paired with low loss of activity during cell-cell transmission (Fig 2B and 2D, S3 Table, S5J Fig). Collectively, this suggests that antibody features that steer high potency against free virus spread are not the driving factors determining the activity during cell-cell transmission.

Bottom Line: Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection.Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs.Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Virology, University of Zürich, Zürich, Switzerland.

ABSTRACT
An increasing number of broadly neutralizing antibodies (bnAbs) are considered leads for HIV-1 vaccine development and novel therapeutics. Here, we systematically explored the capacity of bnAbs to neutralize HIV-1 prior to and post-CD4 engagement and to block HIV-1 cell-cell transmission. Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection. Selection of bnAbs that are capable of suppressing HIV irrespective of the transmission mode therefore needs to be considered to ascertain their in vivo activity in therapeutic use and vaccines. Employing assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission to T cells, we probed a panel of 16 bnAbs for their activity against 11 viruses from subtypes A, B and C during both transmission modes. Over a wide range of bnAb-virus combinations tested, inhibitory activity against HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs. In rare bnAb-virus combinations, inhibition for both transmission modes was comparable but no bnAb potently blocked cell-cell transmission across all probed virus strains. Mathematical analysis indicated an increased probability of bnAb resistance mutations to arise in cell-cell rather than free virus spread, further highlighting the need to block this pathway. Importantly, the capacity to efficiently neutralize prior to CD4 engagement correlated with the inhibition efficacy against free virus but not cell-cell transmitted virus. Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner. In summary, bnAb activity against divergent viruses varied depending on the transmission mode and differed depending on the window of action during the entry process, underscoring that powerful combinations of bnAbs are needed for in vivo application.

No MeSH data available.


Related in: MedlinePlus