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, 6 (5), e1000908

Few and Far Between: How HIV May Be Evading Antibody Avidity


Few and Far Between: How HIV May Be Evading Antibody Avidity

Joshua S Klein et al. PLoS Pathog.

Conflict of interest statement

The authors have declared that no competing interests exist.


Figure 1
Figure 1. Scale model of an IgG antibody.
Red denotes the locations of antigen recognition sites. A longer than typical separation distance (17 nm) was reported for the structure of intact b12 IgG . The longer distance resulted in part from an unusually long CDR3 loop protruding from the antigen-combining site of each Fab. As this loop wraps around the CD4-binding loop on gp120 , the effective separation distance on this IgG and other antibodies with protruding CDR3 loops would be ∼15 nm.
Figure 2
Figure 2. Bar graph of the highest reported molar neutralization ratios (MNRs).
MNRs were reported for monoclonal antibodies against HIV , , , RSV , and influenza , . The MNR for each antibody was calculated as the IC50 of the Fab divided by the IC50 of the IgG derived from in vitro neutralization assays (IC90s were reported for some influenza IgG/Fab comparisons , but IC50 ratios would be nearly the same because the slopes of the inhibition curves were similar). MNRs for a particular IgG/Fab combination can vary with the strain of virus being tested because the degree to which cross-linking can benefit an IgG depends on the affinity of the Fab for its antigen. Differences in size between a Fab and IgG may also influence the MNR if steric factors play a role in the neutralization mechanism of a particular antibody. However, this effect is probably minor, as (Fab)′2 fragments generally exhibit similar neutralization potencies to their parental IgGs , . Not shown are high MNR values (∼70) derived for IgG/Fab comparisons involving HIV virions with a gp41 cytoplasmic tail truncation . The tail deletion, which is rarely observed in vivo, has been suggested to increase the mobility of envelope trimers and/or increase the number of spikes per virion , so its effects on intra-spike cross-linking are not well understood.
Figure 3
Figure 3. Comparison of enveloped viruses and nearest neighbor distances for HIV envelope spikes.
(A) Influenza type A virus. Image provided by Drs. Masashi Yamaguchi and Kuniaki Nagayama. (B) Measles virus. Image reproduced with permission from Dr. Shmuel Rozenblatt from (C) RSV (image credit: US Centers for Disease Control and Prevention). (D) Hepatitis B virus. Image provided by Drs. Kelly Dryden and Mark Yeager. (E) HIV type 1. Image provided by Drs. Ping Zhu and Kenneth Roux. See also . Many schematic pictures of HIV in textbooks and on Web sites show more spikes per virion. Some of these figures were based on early electron micrographs of a mutant simian immunodeficiency virus containing a higher number of spikes per viral particle . Others were based on the incorrect assumption that HIV exhibits icosahedral symmetry. (F) Distribution of nearest neighbor distances between HIV spikes derived from cryo-ET analyses of 40 HIV virions. Data were taken from . Although some spike clustering was reported , the virions exhibited a large distribution of nearest neighbor distances between spikes (7–80 nm center to center).
Figure 4
Figure 4. Bivalent binding model and effect of dissociation rate on neutralization in bivalent and monovalent binding.
(A) Schematic of the step-wise bivalent binding model of an IgG to two envelope spikes (Ag, antigen) tethered to the same surface (kon, association rate constant; koff, dissociation rate constant; kon*, enhanced association rate constant resulting from the small reaction volume of Reaction 2). (B) Comparison of the effect of the Fab dissociation rate constant (koff) on the neutralization potency of Fab (left) and IgG (right) variants of palivizumab, a monoclonal antibody against RSV. Adapted from Table 1 in . The names of the Fab/IgG pairs were changed to A–G for clarity. A, AFFFd; B, AFFYd; C, AFSFd; D, AFFGd; E, W100F; F, S32A; G, wild type (see for an explanation of mutant nomenclature). Note that these results suggest that high affinity Fabs with slow dissociation rates (e.g., Fabs selected by techniques such as phage display) may not exhibit increased neutralization potencies, particularly against a densely packed virus, when converted to bivalent IgGs.

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