Jefferiss Research Trust Laboratories, WrightFleming Institute, Imperial College of Science, Technology and Medicine, St Marys Campus, Norfolk Place, London W2 1PG, UK1
Author for correspondence: P. J. Klasse. Fax +44 20 7594 3906. e-mail p.klasse{at}ic.ac.uk
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Abstract |
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Introduction |
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Virus neutralization by antibody |
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Antibodyvirus binding |
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Over a wide range of virion concentrations, a given concentration of Ab neutralizes the same relative proportion of virus infectivity (Andrewes & Elford, 1933 ). This finding was referred to as the percentage law but it is really the expected effect of Ab excess over Ag, which makes the fraction of complexed Ab negligible (Burnet et al., 1937
). Indeed, as described for human cytomegalovirus (HCMV), increasing the virion concentration 100-fold (keeping the infectious dose constant by adding inert particles) does not affect the titre of cross-neutralizing sera (Klein et al., 1999
). The explanation for this would be the relatively constant Ab occupancy on the virions. The relative occupancy of viral epitopes can be defined as the proportion ligated by a paratope. It is central to the analysis of neutralization that under ordinary assay conditions this relative occupancy is approximately determined by the total Ab concentration and its functional affinity for epitopes as presented on the virion (Fig. 1
) (Klasse, 1996
).
In a study of the Ab response during infection with VSV in mice, the neutralizing capacity of the sera was found to correlate better with the on-rate constant of binding (Fig. 1) than with affinity (Roost et al., 1995
). Studies of human immunodeficiency virus type 1 (HIV-1) indicate that the on-rate of Ab binding to the oligomeric form of the envelope (Env) glycoprotein is more important with respect to neutralization than the affinity is (Fouts et al., 1997
; Sattentau & Moore, 1995
). The influence of the on-rate would also explain why neutralization is less potent the shorter the pre-incubation of Ab and virus is before mixing with the target cells (Burnet et al., 1937
; Della-Porta & Westaway, 1978
; McDougal et al., 1996
). All of these findings are nevertheless consonant with the requirement of a certain Ab occupancy on the virions, whether at equilibrium or before, in order to abrogate infectivity. It was stated succinctly That the survival or inactivation of a given virus particle is determined by the amount of antibody combined with it at the moment of effective contact with the susceptible cell (Burnet et al., 1937
). Because of the bound Ab, this effective contact may, of course, not arise; but it is important to take potential competition between Ab and receptors on the surface of the susceptible cell into account. And such competition would be subject to the influence of the kinetic constants of Ab binding to virus. However, much less emphasis has been placed on the potentially crucial rate constants of Ab and receptor binding by virus than on the kinetics of the neutralization reaction itself.
For nearly half a century, kinetic analyses of neutralization have dominated theories of how many Ab molecules must bind per virion in order to neutralize (Dulbecco et al., 1956 ). Recently, we have criticized the theoretical and empirical basis of these influential ideas (Klasse & Sattentau, 2001
). The central arguments about kinetics, stoichiometry and occupancy are illustrated in Fig. 2
.
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Mechanisms of neutralization |
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Interference with virus attachment and virusreceptor interactions
Virus attachment is necessary for infection: blocking that step pre-empts the entry process. This mechanism is important in the neutralization of many naked and enveloped viruses (reviewed by Burton et al., 2001 ; Klasse & Sattentau, 2001
; Parren & Burton, 2001
; Smith, 2001
). Certain Abs prevent the extracellular enveloped form of vaccinia virus from attaching to target cells (Law & Smith, 2001
). Likewise, several Abs to gp120, the outer Env protein of HIV-1 (Fig. 4a
), block attachment of the virus to CD4+ T-cell lines regardless of whether they are directed to epitopes directly involved in interactions with CD4, the primary receptor for the virus (Ugolini et al., 1997
). However, a mAb to the transmembrane protein, gp41, recognizing intact Env spikes, neutralizes well without any detectable effect on virus attachment. This differential effect by the generally attachment-blocking gp120 mAbs and the gp41 mAb that allows neutralized virus to attach to cells could be attributed to differences in the proximity of the bound mAb to the viral membrane and in the angle of binding to different components of the Env protein spikes (Figs 3
and 4
). A comparison could be made with two mAbs to papillomavirus, which show differential effects on virus attachment to cells: one binds bivalently and deeply between hexavalent capsomeres and only partially blocks attachment, whereas the other mAb binds monovalently to the outer surface of pentavalent capsomeres and completely blocks virus attachment (Booy et al., 1998
). Abs to different sites on La Crosse virus prevent attachment to cells in various degrees, which only partly explains their neutralizing capacity (Kingsford et al., 1991
). Likewise, nAbs to different Ags on the surface of rotavirus inhibit virus attachment to varying extents (Ruggeri & Greenberg, 1991
).
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Neutralization epitopes on the influenza virus haemagglutinin (HA) surround the receptor-binding pocket. This suggests that neutralization interferes with receptor binding and that mutations at these sites may abrogate Ab binding but not the docking of the receptor into its pocket (Skehel & Wiley, 2000 ). For some viruses, the situation is more complicated: in these instances, different viral receptors are required for attachment to the cell surface and entry. Certain viruses, including herpes simplex virus (WuDunn & Spear, 1989
) and foot-and-mouth disease virus (FMDV) (Fry et al., 1999
), make use of ancillary receptors, such as heparan sulphate proteoglycans, for initial tethering to the target cell; they rely on other molecules for internalization or triggering of fusion (Ugolini et al., 1999
). Some viruses, e.g. adenovirus and HIV, interact with co-receptors as a step in the entry process. All of these interactions are potential targets for nAbs, which may interfere with the attachment process in various degrees. Indeed, most HIV-1 gp120-specific nAbs block either CD4gp120 binding or co-receptorgp120 binding, or both (Mondor et al., 1998a
; Trkola et al., 1996
; Wu et al., 1996
). The Env glycoprotein of bovine leukaemia virus, a deltaretrovirus, is prevented from binding to a recombinant form of the receptor for the virus, BLVRcp1, by sera from infected cattle but not by some mAbs to Env (Orlik et al., 1997
). It is uncertain how either kind of Ab would affect virus attachment to permissive cells.
We have given several examples of nAbs that act by blocking virus attachment to cells after Abvirus pre-incubation and some nAbs that do not. Such effects are independent of a capacity of certain Abs for blocking infection of virus that has already absorbed to target cells (Mandel, 1978 ; Armstrong et al., 1992; Lu et al., 1992
; Vrijsen et al., 1993
; Pelchen-Matthews et al., 1995
; Armstrong et al., 1996
; McInerney et al., 1997
; Edwards & Dimmock, 2001a
). This capacity does not imply that the Abs block the same step at physiological temperature or when present before the viruscell encounter: several Abs that can block attachment are also capable of neutralizing after the virus has adsorbed to cells at a temperature that does not allow entry. Furthermore, it should be addressed experimentally whether Abs added after virus attachment can bring about the detachment of pre-adsorbed virions from target cells (Dietzschold et al., 1987
; Ruggeri & Greenberg, 1991
; Edwards & Dimmock, 2001a
): i.e. does post-attachment neutralization act by reversing attachment?
In conclusion, although many Abs interfere both with virusreceptor interactions and with attachment, particular Abs that block receptor interactions may neutralize without blocking virus attachment to certain cell types, whereas others that do not directly interfere with receptor binding of viral proteins block attachment of virions to cells (Massey & Schochetman, 1981b ; Linsley et al., 1988
; McInerney et al., 1997; Ugolini et al., 1997
; Mondor et al., 1998b
; Klasse & Sattentau, 2001
; Smith, 2001
). Interference with receptor interactions subsequent to virus attachment can also effect neutralization (Armstrong & Dimmock, 1996
; Armstrong et al., 1996; Lu et al., 1992
). Regardless of this, when blockage of attachment does occur, whether through direct occlusion of sites involved in virus binding to cells or indirectly through steric interference by Ab coating of the virions, then infection is by necessity prevented.
Induction of conformational changes by nAbs
The binding of some Abs to the capsid of picornaviruses results in conformational changes, which are reflected in a shift in the isoelectric pH, the pI, of the virions (Che et al., 1998 ; Mandel, 1976
, 1978
; Smith, 2001
). However, this effect does not correlate with the extent of neutralization (Brioen et al., 1985b
); the pI shift is not a prerequisite for the neutralization of rhinoviruses (Smith, 2001
). Rather, whereas the paratope of one strongly neutralizing Fab undergoes significant conformational changes when it binds, the epitope itself is left essentially unchanged (Smith et al., 1996
). Furthermore, although Abs to four different neutralization epitopes on the rhinovirus capsid effect the pI changes when they bind, they are unlikely to cause similar conformational changes because of their disparate sites and modes of binding (Colonno et al., 1989
). They would be most likely to affect the conformation of distinct, flexible loop regions and not the protein core. Abs to picornaviruses can stabilize virions against changes induced by low pH and such changes may be necessary for infection via the endosome. But these stabilizing Abs, whether aggregating or not, neutralize rhinovirus to widely differing extents (Che et al., 1998
). Moreover, Abs of other specificities do not block pH-induced changes, yet neutralize well. It therefore seems telling that Abs to all the rhinovirus neutralization epitopes are instead capable of preventing cellular attachment of the virus (Colonno et al., 1989
), thus blocking a step prior to internalization and pH-induced changes. The hypothesis of neutralization through capsid stabilization implies that some mutations would mediate escape from neutralization by specifically preventing such stabilizing effects. Yet all the neutralization-escape mutants of rhinovirus that have been analysed show impaired Ab binding compared with wild-type (Smith, 2001
). Hence, conformational changes induced by nAbs may constitute dispensable epiphenomena.
The study of HIV-1 provides some examples of Ab-induced conformational changes that are not necessary for neutralization but may nevertheless affect it. One of the most potent nAbs (IgG1 b12), which is directed against the outer Env protein gp120, binds to an epitope that overlaps with the CD4-binding site (Burton et al., 1994 ). Whereas CD4 induces conformational changes in gp120 (Moore et al., 1990
), the Ab does not (Poignard et al., 1996
) but rather appears to recognize an epitope that is present on the native conformation of the antigen (Saphire et al., 2001
). However, several other Abs to gp120 affect the conformation of the Env complex when they bind, as demonstrated by their induction of gp120 shedding from the transmembrane glycoprotein, gp41 (Fig. 4a
) (Poignard et al., 1996
). When such shedding occurs, the number of functional Env oligomers on the virion decreases. There is evidence that spontaneous dissociation of gp120 makes the virus more sensitive to neutralization by soluble CD4 (Layne et al., 1990
), as explained by an occupancy model of neutralization (Klasse & Moore, 1996
). However, the model predicts that the same degree of neutralization would be achieved by a higher-affinity Ab that does not induce dissociation (Fig. 5b
). A complication is that the indirect steric effect of a bound Ab would disappear with the Ag, thus giving a weaker neutralizing effect on neighbouring spikes than an Ab that does not induce shedding. The net effect cannot be calculated on the basis of our present knowledge.
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High-occupancy theories of neutralization |
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A meticulous investigation of rabies virus neutralization provides an example of multiple-hit molecularity. Neutralization of rabies virus requires occupancy by more than 200 IgG or 40 IgM molecules per virion (Flamand et al., 1993 ). An average of 130 IgG or 30 IgM per virion gives little or no neutralization; 37% relative infectivity (an arbitrary figure for these multi-hit molecularities) is obtained at 130320 IgG or 4050 IgM. In relative terms, these levels of Ab binding would correspond to occupancies of >30% for IgG and 50% for IgM, defined as proportions of actual binding over maximal possible binding (i.e. saturation). According to another definition of relative occupancy, i.e. the fraction of epitopes occupied by paratopes, the maximum relative occupancy can then be well below 100% because steric hindrance may prevent some epitopes from being occupied at saturation. The gap between the two definitions begs the question whether maximal binding of Ab can leave such a high fraction of unoccupied epitopes (because of steric constraints) that it is non-neutralizing. The adenovirus fibre Ag may cause steric hindrance of this kind: the significant proportion of unoccupied penton-base epitopes at saturating Ab concentrations could explain the lack of neutralization by certain Abs (Stewart et al., 1997
; Stewart & Nemerow, 1997
). This would also account for the unusual situation that the Fab neutralizes while the IgG does not (Fig. 1b
). A more complex and intriguing relationship between IgG and Fab neutralization has been described for influenza virus: in one case, an IgG neutralizes partly by blocking virus attachment and more efficiently than its Fab, which only prevents fusion, although they have similar functional affinities for the HA Ag. In other cases, the Fabs are found to neutralize exclusively by blocking attachment, while the corresponding IgGs interfere both with attachment and with fusion. Nevertheless, all are capable of preventing infection after virus adsorption (Edwards & Dimmock, 2000
, 2001a
, b
). Future studies may specifically dissect the effects of valency and Ab bulk on binding and interference with attachment and fusion or penetration of different viruses.
The study of rabies virus provides another important test case for neutralization hypotheses: Abs that specifically recognize a minority conformation of spike proteins do not neutralize at physiological pH. However, if all of the spike protein is converted to this antigenic conformation by a lowering of the pH, then the Abs neutralize (Flamand et al., 1993 ; Raux et al., 1995
). This refutes the simplistic view that all Abs that can bind to functional virus surface molecules involved in entry or attachment will necessarily neutralize: it suggests instead that a certain minimum proportion of such molecules must be blocked for neutralization to occur.
Neutralization by antibody coating
Burton and colleagues (Burton et al., 2001 ; Parren & Burton, 2001
) have investigated the relationship between the surface area on virions and the number of Ab molecules required for neutralization, where these data can be extracted with some confidence from the literature. For five different viruses, and even when the larger, non-virus pathogen Chlamydia trachomatis is included, there is an approximately linear relationship between the number of nAbs required to neutralize the majority of the infectivity and the particle surface area. This supports the coating theory proposed by the authors: neutralization of viruses is due to steric or direct blocking of a proportion of the virion surface such that the requisite interactions between virus and the cellular membrane are prevented.
The coating theory explains why Abs to non-viral molecules on the virion surface can neutralize infectivity. It has interesting implications also for the incorporation into viral envelopes of viral proteins that are not required for infection. For example, Abs to influenza virus neuraminidase (NA) and the M2 protein do not neutralize but block release of progeny virions (Webster & Laver, 1967 ; Kilbourne et al., 1968
; Zebedee & Lamb, 1988
). Does the demonstration of Abs that bind to these Ags on the virion surface but still do not neutralize refute the coating theory of neutralization? As pointed out recently, the receptor-binding and fusogenic HA protein is vastly more abundant than either NA or M2 on the virion surface; furthermore, NA is unevenly distributed over the virion surface (Parren & Burton, 2001
). Therefore, the maximal occupancy on these Ags may not be able to cause steric interference with entry functions. However, the coating theory implies that at a higher density of NA molecules, such Abs would become neutralizing (Fig. 5c
); likewise, a potentiating effect of NA Abs on neutralization by HA Abs could be predicted. One can ask whether the density of viral Ags that do not mediate entry is kept down by a selective pressure.
An illustrative example of the effects of non-viral, non-essential molecules is the incorporation of the intercellular adhesion molecule 1 (ICAM-1) in HIV-1 particles (Rizzuto & Sodroski, 1997 ). The presence of ICAM-1 enhances infection of CD4+ T-cells; it makes the virus less sensitive to anti-Env neutralization and highly susceptible to an Ab against ICAM-1. The reduction in infectivity by the ICAM-1 Ab is several-fold greater than the enhancement of infectivity by the presence of ICAM-1. Thus, the ICAM-1 Ab interferes not just with an auxiliary ICAM-1 function in infectivity but collaterally with Env function. Furthermore, truncation of the cytoplasmic tail of simian immunodeficiency virus Env reduces incorporation of HLA-I, -II and co-expressed influenza virus HA; neutralization by Abs to these non-HIV molecules decreases accordingly (Vzorov & Compans, 2000
). This substantiates the coating theory, which implies that a dense coat of Ab over the virion surface will interfere by steric hindrance with the function of unoccupied viral molecules.
Neutralization of bovine papillomavirus by different Abs requires different occupancies (Roden et al., 1994 ). This is attributable to differences in the distribution of sites over the virion surface, mono- or bivalent binding and the angle of projection from the virion of the bound Ig molecule. Furthermore, one-point binding in a protruding manner coincides with blocking of virus attachment, while bivalent binding that is more flush with the virion surface neutralizes at least partly by a post-attachment mechanism (Booy et al., 1998
). Such subtle effects of valency and orientation of bound Ab (Hewat & Blaas, 1996
; Hewet et al., 1998
) may explain why there are deviations from linearity in the plot of the minimum number of Abs per virion required for neutralization (Burton et al., 2001
). But if the area of virion surface that is occluded by Ab could be measured for different modes of Ab binding, then the areastoichimetric relationship would be testable with some precision. A refinement of the high-occupancy or coating theory could be formulated thus: neutralization occurs when the number of unencumbered entry-mediating viral molecules is brought below a required minimum by Ab occupancy. This would imply only approximate linearity in the plot of the number of Ab molecules needed as a function of virion area. As structural and stoichiometric data for more viruses become available, it will be possible to test whether the number of functional entry-mediating viral protein units per virion correlates better than does virion area with the minimal number of neutralizing Ab molecules (Fig. 5
).
It has been suggested previously that occupancy of one monomeric subunit by one Ab paratope may be sufficient to knock out the function of the entire HIV Env trimer and potentially also that of adjacent trimers (Klasse & Moore, 1996 ). If there is a minimum number of necessary Ag molecules required for infection, then the higher their density, the greater the minimal occupancy needed for neutralization (Fig. 5
). In the case of HIV, this seems to be the case (Layne et al., 1990
): shedding of the outer Env protein gp120 increases neutralization sensitivity. The tendency of some strains of HIV-1 to shed their Env (Moore et al., 1990
) could provide a testing ground for refinement of the coating theory. When the outer Env protein, gp120, is shed, it converts a functional spike to an inert one while exposing epitopes on the transmembrane protein, gp41. Although these epitopes are strongly immunogenic in natural infection, Abs directed to them are generally not neutralizing or only weakly so (Gnann et al., 1987
; Ho et al., 1987
; Bugge et al., 1990
; McDougal et al., 1996
; Verrier et al., 2001
; Wilson et al., 1990
). The coating theory explains this on the basis that the density of transmembrane protein spikes on the virion is too low to achieve a neutralizing Ab coat. Alternatively, the lack of neutralization could be due to the functional inertia of such spikes in combination with their too long distance from functional spikes. Thus, with increased shedding (as long as it remains compatible with infectivity), neutralization by these gp41 Abs could become significant if non-specific coating were responsible; or, on the contrary, there would be no added effect, if proximity to functional spikes were insufficient. Abs to gp120 would decrease in potency with shedding because of less general coating and neighbour blocking effects; or, alternatively, their potency would increase because the required occupancy would be lower when the virions have fewer spare spikes (Fig. 5
). This example illustrates that the coating theory can be formulated in more precise versions with distinct test implications.
There are qualitative complications of steric hindrance by coating: the angle and valency of Ab binding, as well as the bulkiness of the Fc portion, can influence the area of virion surface that is blocked. The mobility of the epitope and of the Ab bound to it might influence the size of the virion-surface area that is prevented from functional interactions. However, two mAbs that bind to the same highly mobile loop on FMDV, one in a fixed manner, the other allowing loop flexibility, neutralize the virus with indistinguishable efficiency (Hewat et al., 1997 ; Verdaguer et al., 1999
). A mAb that binds human rhinovirus bivalently with a maximum of 30 molecules per virion neutralizes the virus to a great extent; other nAbs that bind monovalently at a maximum of 60 molecules per virion neutralize and aggregate the virus to highly divergent degrees (Smith et al., 1993
; Smith, 2001
). These differences are not readily attributable to variable functional affinities since they occur at saturating mAb concentrations. Neutralization of papillomavirus to half-maximal extent by one bivalently and one monovalently binding mAb requires the occupancy of similar numbers of epitopes and roughly twice as many molecules of the latter as of the former (Booy et al., 1998
). Once the functional affinity factor is controlled for by comparison of similar actual occupancies, a prediction from the coating theory could be that the thicker coat of monovalently bound antibody would neutralize to a greater extent. Since this is not the case, perhaps dynamic factors such as stability of Ab binding and competition by cellular receptors may have to be invoked in a satisfactory occupancy theory of neutralization.
Although aggregation is not a universal effect of the binding of efficient nAbs (Che et al., 1998 ), it can qualify as a mechanism of neutralization. Therefore it is pertinent here to point out its relationship to occupancy. Aggregation requires at least bivalent antibody binding that links virus particles into lattices. Such cross-linking typically occurs at intermediate Abvirus ratios, so that the prevalence of non-aggregated virus describes a U-shaped relationship to Ab concentration. A corresponding U-shaped virus survival curve would refute the coating theory, since non-aggregation at higher Ab concentrations is explained by saturation of all epitopes by monovalently binding Ab. As the aggregates are broken up by excess Ab, however, infectivity sometimes increases but is not completely restored (Thomas et al., 1986
; Smith, 2001
). The coating theory thus survives this test.
Antibody coating and virus escape
Can the modes of virus escape refute or corroborate the coating theory of neutralization? A high-occupancy theory implies that a decrease in the affinity of the nAb for the target antigen will readily mediate virus evasion. This is indeed a prevalent mode of escape (reviewed by Smith, 2001 ; Bizebard et al., 2001
). If the affinity is not reduced, neutralization insensitivity could instead be due to an increased difference between the total and minimally required numbers of functional viral surface proteins involved in attachment and entry functions (Klasse & Moore, 1996
). Predicted escape mechanisms derived from the non-specific coating effect would be a decrease in the density of Ab binding sites or a change in the mode of Ab binding, such that a smaller area of the viral surface is blocked sterically at a certain occupancy. A neutralization-escape mutant of HCMV may be a case in point. The escape phenotype coincides with a reduction in the number of copies of the gH protein on the viral surface. In the absence of selection, there is swift reversion to neutralization sensitivity (Li et al., 1995
). It would be crucial to determine whether the mutant has switched from dependence on gH for mediating entry.
In the field of HIV research, what might be understood as the reverse of escape from neutralization has come to the fore. Primary isolates (PI) of HIV are substantially more resistant to neutralization than T-cell line-adapted (TCLA) strains obtained by reiterated passage in vitro (Moore & Ho, 1995 ). One factor that determines this difference may be the absence of nAbs in vitro: their presence in vivo may constitute a selective pressure that maintains the resistant phenotype. Other characteristics of the in vitro growth conditions may select for phenotypic traits that entail the neutralization-resistant phenotype as a mere contingency. In either case, resistance may be mediated by a relative inaccessibility of the neutralization epitopes on the Env oligomers as presented on the virion surface (Fig. 4
) (Parren & Burton, 2001
; Poignard et al., 1996
; Sattentau et al., 1999
). Such relative inaccessibility would simply reduce the functional affinities of the Abs for their epitopes. Thereby only subneutralizing occupancies might be achieved at ordinary Ab concentrations. The explanation is consonant with a requirement for high occupancy and hence with the coating theory.
Some mAbs that do not neutralize rabies virus under ordinary conditions will do so at lower pH, at higher temperature or after prolonged incubation. These conditions presumably allow the sufficiently prevalent adoption of antigenic conformations of the relevant epitopes. Mutants resistant to this special neutralization have been selected (Raux et al., 1995 ). The mechanism of resistance may be prevention of a conformational change in the majority of the molecules or it may make the changed conformation non-antigenic. In either case, an occupancy of too few spikes on the mutant virus for neutralization to occur would explain the resistance (Raux et al., 1995
).
However, another neutralization escape mutant of rabies virus poses a further challenge to the coating theory. Although this mutant can bind over 1000 IgG molecules per virion, it is still completely resistant to neutralization (Flamand et al., 1993 ). Whether the Ag to which the Ab binds still performs its function in attachment and entry or the mutant has adopted alternative strategies is unknown. It also remains to be determined whether the few unoccupied epitopes at Ab saturation are somehow more accessible and functional than on wild-type virus, whether the orientation of bound Ab is affected by the escape mutation and whether a kinetic difference in binding allows receptor competition with Ab on the mutant. Answers to these questions could either refute or corroborate differentiated hypotheses of neutralization as mediated by general coating of virions or, alternatively, by specific interference with the function of Ags involved in virus entry and attachment. However, it should be remembered that this potential exception to the general rule that high occupancy effects neutralization is a viral mutant and not a naturally occurring virus.
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Conclusion |
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Theoretical and empirical support is strong for inhibition of virus attachment and early entry functions as dominant mechanisms of neutralization. Likewise, multi-hit molecularities of neutralization, as well as viral escape through mutations that decrease Ab affinity, are well substantiated for several viruses. Occupancy of Ab on the viral surface is thus central to theories of neutralization. High occupancy of Abs on viral or other Ags may form blocking coats around the virion. Future research may elucidate the requirements for the density of the Abs and for their contiguity to functionally crucial sites on the virion. An improved understanding of neutralization and virus escape from it will inform the selection and modification of immunogens in vaccine design with the aim of eliciting optimal nAb responses.
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Acknowledgments |
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References |
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