3D structure model of the principal neutralizing epitope of Minnesota HIV-1 isolate

A hierarchical procedure, using a "bottom-up" strategy and combining (i). a probabilistic approach for estimating all possible starting structures, (ii). restrained molecular mechanics algorithms for preliminary selection of all energetically preferred conformers, as well as (iii). quantum chemical computations for refining their geometry, was used to study the structural properties of the HIV-MN neutralizing epitope in terms of NMR spectroscopy data. As a result, only one of initial structures matching the experimental and theoretical data was found to be well-ground for implementing the function of immunoreactive conformation of the virus immunogenic crown. The geometric parameters of this structure in water solution were shown to correspond to a double beta-turn conformation similar to that revealed in crystal for synthetic molecules imitating the central region of the HIV-MN V3 loop. The following conclusion was drawn from the comparative analysis of simulated structure with the one computed previously: the HIV-MN immunogenic tip has some inherent conformational flexibility that manifests at the alterations of hexapeptide environment and leads to the structural transitions changing the local conformation of the stretch of interest but retaining its spatial main chain fold. As a matter of record, the high resolution 3D structure model for the HIV-MN principal neutralization site was constructed, and its geometric parameters were compared with the corresponding characteristics of conformers derived earlier for describing the conformational features of immunogenic tip of gp120 from Thailand HIV-1 isolate.     

Modeling of the 3D structure of the HIV-Haiti immunodominant epitope

The 3D structure for the HIV-Haiti immunodominant epitope was computed in terms of NMR spectroscopy data using the theoretical procedure including a probabilistic approach in conjunction with molecular mechanics algorithms and quantum chemical methods. The immunogenic crown of the virus protein gp120 was shown to form in solution a prevalent conformation whose geometric parameters match the double beta-turn IV-IV. Two structures observed in crystal were found in the ensemble of the best-energy conformations of the HIV-Haiti principal neutralizing epitope. From a comparison of simulated structures with those computed previously for the HIV-Thailand and HIV-MN isolates, it was concluded that the immunogenic tip of gp120 gives rise to similar spatial backbone forms in different HIV-1 strains but has some inherent conformational flexibility of its individual amino acid residues. The differences in local fragment structures revealed in three isolates of HIV-1 are supposed to be important for the specificity of its binding with neutralizing antibodies.     

Dual spatial folds and different local structures of the HIV-1 immunogenic crown in various virus isolates

Local and global structural properties of the HIV-1 principal neutralizing epitope were studied in terms of NMR spectroscopy data reported in literature for the HIV-Haiti and HIV-RF isolates. To this effect, the NMR-based method comprising a probabilistic model of protein conformation in conjunction with the molecular mechanics and quantum chemical computations was used for determining the ensembles of conformers matching the NMR requirements and energy criteria. As a matter of record, the high resolution 3D structure models were constructed for the HIV-Haiti and HIV-RF immunogenic crowns, and their geometric parameters were collated with the ones of conformers derived previously for describing the conformational features of immunogenic tip of gp120 from Thailand and MN HIV-1 strains. The HIV-1 neutralization site was demonstrated to constitute in water solution highly flexible system sensitive to its environment. This inference is completely valid for the geometric space of dihedral angles where statistically significant differences in local structures of simulated conformers have been found for all virus isolates of interest. In spite of this fact, the stretch analyzed was shown to manifest a certain conservatism in the space of atomic coordinates, building up in four HIV-1 isolates two spatial folds similar to those observed in crystal for the V3 loop peptides bound to different neutralizing Fabs. The results are discussed in the light of literature data on HIV-1 neutralizing epitope structure.     

Structure and Polymorphism of the Principal Neutralization Site of Thailand HIV-1 Isolate

Abstract

Refining the geometric parameters for the ensemble of conformers, derived earlier in terms of NMR-spectroscopy data for the immunogenic tip of Thailand HIV-1 isolate, was carried out by quantum chemical methods. As a result, (i) the energy characteristics of initial structures were significanly improved, (ii) their relative locations on the scale of formation heats were determined, and (iii) the energy barriers between conformers under study were computed. On the basis of all data obtained, the high resotion 3D structure model, describing the set of stable conformers and containing the biologically active conformation, was proposed for neutralizing epitope of Thailand HIV-1 isolate. The following major conclusions were made based on the analysis of simulated conformations: i) the Gly-Pro-Gly-Gln-Val-Phe stretch forming the immunogenic crown of Thailand HIV-1 isolate exhibits the properties characteristic for metastable oligopeptide that constitutes in solution the dominant structure with other conformations admissible; (ii) three structures out of five NMR-based starting models form the cluster of conformers which adequately describes general conformational features of this functionally important site of gp120; (iii) two structures residing in this cluster are found to be well-ground for implementing the function of immunoreactive conformation of the stretch of interest; (iv) in spite of this observation, the “global” structure which gives rise to inverse γ-turn in the central Gly-Pro-Gly crest of Thailand HIV-1 gp120 is proposed to be the most probable conformation responsible for the formation of viral antigen-antibody complex in particular case under study.     

Structure and polymorphism of the principal neutralization site of Thailand HIV-1 isolate

Refining the geometric parameters for the ensemble of conformers, derived earlier in terms of NMR-spectroscopy data for the immunogenic tip of Thailand HIV-1 isolate, was carried out by quantum chemical methods. As a result, (i) the energy characteristics of initial structures were significantly improved, (ii) their relative locations on the scale of formation heats were determined, and (iii) the energy barriers between conformers under study were computed. On the basis of all data obtained, the high resolution 3D structure model, describing the set of stable conformers and containing the biologically active conformation, was proposed for neutralizing epitope of Thailand HIV-1 isolate. The following major conclusions were made based on the analysis of simulated conformations: i) the Gly-Pro-Gly-Gln-Val-Phe stretch forming the immunogenic crown of Thailand HIV-1 isolate exhibits the properties characteristic for metastable oligopeptide that constitutes in solution the dominant structure with other conformations admissible; (ii) three structures out of five NMR-based starting models form the cluster of conformers which adequately describes general conformational features of this functionally important site of gp120; (iii) two structures residing in this cluster are found to be well-ground for implementing the function of immunoreactive conformation of the stretch of interest; (iv) in spite of this observation, the "global" structure which gives rise to inverse gamma-turn in the central Gly-Pro-Gly crest of Thailand HIV-1 gp120 is proposed to be the most probable conformation responsible for the formation of viral antigen-antibody complex in particular case under study.     

Local structural properties of the V3 loop of Thailand HIV-1 isolate

The model of locally accurate conformation for the HIV-Thailand principal neutralizing determinant (PND) located within the V3 loop of the virus envelope protein gp120 was built in terms of NMR spectroscopy data. To this end, the NMR-based conformational analysis of synthetic molecule representing the peptide copy of the fragment under study was carried out using the published sequential d connectivity data and values of spin-spin coupling constants. As a result, (i) the local structure for the V3 loop from Thailand isolate was determined, (ii) the conformations of its irregular segments were analyzed, and the secondary structure elements identified, (iii) the ensemble of conformers matching the experimental and theoretical data was derived for the stretch forming the neutralizing epitope of the HIV-Thailand PND, (iv) to estimate the probability of realizing each of these conformers in solution, the results obtained were collated with the X-ray data for corresponding segments in synthetic molecules imitating the central region of the HIV-MN PND as well as for homologous segments 39-44 in Bence-Jonce REI protein (BJRP), 41-46 in immunoglobulin lambda (Ig lambda), and 50-55 in beta-chain of horse hemoglobin (HH), (v) to find the conserved structural motifs inside diverse HIV-1 isolates, the structure determined was compared with the one derived earlier for the HIV-MN PND from NMR spectroscopy data, (vi) on the basis of all data obtained, the 3D structure model describing the set of biologically relevant conformations, which may present different antigenic determinants to the immune system in various HIV-1 isolates, was proposed for the immunogenic crown of the V3 loop. The results obtained are discussed in conjunction with the data on the structure for the HIV-1 PND reported in literature.     

Global and Local Structural Properties of the Principal Neutralizing Determinant of the HIV-1 Envelope Protein gp120

Abstract

The model of spatial structure for the principal neutralizing determinant (PND) of the HIV-1 envelope protein gpl20 is proposed in terms of two-dimensional nuclear Overhauser effect (NOE) spectroscopy data. To build the model, the NMR-based theoretical conformational analysis of synthetic PND peptides of length 40, 24, and 12 residues is carried out. The modeling of the molecular spatial structures is performed by a new approach to research of conformationally mobile peptides using the algorithms of the restrained molecular mechanics method developed earlier. The following major conclusions are made based on the analysis of the simulated peptide conformations: i) there is not unique PND structure in solution, ii) there are seven different PND structures each of which agrees with the experimental data and stereochemical criteria used in computing its spatial model, iii) the PND is characterized by irregular conformation containing a number of reverse turns, iv) all of the selected conformations are conserved in the Gly-Pro-Gly-Arg-Ala-Phe stretch, the most provable viral immunodominant epitope. These data allow to suppose that binding properties of this site are determined by the structural motif which forms the conformation of a double β-turn and appears common for all hexapeptide structures.     

Immunophilins and HIV-1 V3 Loop For Structure-Based Anti-AIDS Drug Design

Abstract

The model of the structural complex of cyclophilin A (CycA) belonging to the immunophilins family with the HIV-MN gpl20 V3 loop was generated, and the computer-aided design of the immunophilin-derived peptide able to mask the biologically crucial V3 segments was implemented.

To this end, the following problems were solved: (i) the NMR-based conformational analysis of the HIV-MN V3 loop was put into effect, and its low energy structure fitting the input experimental observations was determined; (ii) molecular docking of this V3 structure with the X-ray conformation of CycA was carried out, and the energy refining the simulated structural complex was performed; (iii) the matrix of inter-atomic distances for the amino acids of the molecules forming part of the built over-molecular ensemble was computed, the types of interactions responsible for its stabilization were analyzed, and the CycA stretch, which accounts for the binding to V3, was identified; (iv) the most probable 3D structure for this stretch in the unbound state was predicted, and its collation with the X-ray structure for the corresponding site of CycA was performed; (v) the potential energy function and its constituents were studied for the structural complex generated by molecular docking of the V3 loop with the CycA peptide offering the virtual molecule that imitates the CycA segment, making a key contribution to the interactions of the native protein with the HIV-1 principal neutralizing determinant; (vi) as a result of the studies above, the designed molecule was shown to be capable of the efficacious blockading the functionally crucial V3 sites; and (vii) based on the joint analysis of the evidence obtained previously and in the present study, the composition of the peptide cocktail presenting the promising anti-AIDS pharmacological substance was developed.

The molecules simulated here by molecular modeling methods may become the first representatives of a new class of the chemical compounds (immunophilin-derived peptides) offering the looking-forward basic structures for the design of efficacious and safe antiviral agents.     

Modeling of the spatial structure of an HIV-haiti immunodominant epitope

A model of the spatial structure of the immunodominant epitope of human immunodeficiency virus type 1 (HIV-Haiti virion) consistent with the NMR data was constructed using an earlier proposed method based on theoretical calculations. It was found that, in aqueous solution, the main immunogenic region of the virus protein gp120 took the prevalent conformation of a double β-turn IV–IV. It is shown that two structures of this fragment found in the crystal were present in the set of preferable conformations of the HIV-Haiti immunodominant epitope. On the basis of comparative analysis of the 3D structures of the immunodominant epitopes of type 1 human immunodeficiency virus (HIV-Haiti, HIV-Thailand, and HIV-MN virions), it was concluded that the studied gp120 fragment forms similar spatial backbone structures in these three virus subtypes; however, these structures are formed from different local minimums of the constituent amino acids. It was assumed that the detected distinctions between the local structures of this fragment determine the specificity of HIV-1 binding to virus-neutralizing antibodies.     

Model of three dimensional structure of the immunodominant epitope of gp120 HIV(Thailand)

The geometry of five preferred structures of the immunodominant epitope of the HIV(Thailand) protein gp120, derived earlier from the NMR spectroscopy data, was refined using the quantum chemical methods. As a result, (i) the energy characteristics of the initial structures were improved significantly, (ii) their relative locations on the scale of formation heats were determined, and (iii) the energy barriers dividing the conformers under study were computed. On this basis, only two out of five starting structures were proposed as biologically relevant conformations for the virus immunogenic crown. The results obtained are discussed in connection with the literature data on the structure of the HIV-1 principal neutralizing determinant.     

Design and characterization of a germ-line targeting soluble,native-like,trimeric HIV-1 Env lacking key glycans from the V1V2-loop

BackgroundThe HIV-1 envelope glycoprotein (Env) is the primary target for broadly neutralizing antibodies (bNAbs) which can block infection. The current design strategy of soluble forms of Env in native-like trimeric conformation induces neutralizing antibodies with minimal breadth and potency. Extensive shielding by N-glycans on the surface of the HIV-1 Env acts as an immune evasion mechanism by restricting B cell recognition of conserved neutralizing determinants. An alternate approach is to design Env protein with glycan deletion to expose the protein surface.MethodsA stable native-like trimeric Env with glycan holes at potentially immunogenic locations is expected to elicit better induction of germ-line B-cells due to exposure of the immunogenic regions. However, the extent and consequences of glycan removal from the trimer apex that form an important epitope is not explored. In this work, we have designed a construct with glycans deleted from the trimer apex of an Indian clade C origin Env that has previously been characterized for immunogenicity, to understand the impact of deglycosylation on the structural and functional integrity as well as on the antibody binding properties.ResultsThe V1V2 glycan-deleted protein maintains native-like trimeric conformation with improved accessibility of the V1V2-directed germ-line antibodies. Furthermore, we showed that the protein binds specifically to quaternary conformation-dependent bnAbs but minimally to non-neutralizing antibodies.ConclusionsThis study provide an important design aspect of HIV-1 Env-based immunogens with glycan holes in the apex region that could be useful in eliciting apex directed antibodies in immunization studies.     

Global and local structural properties of the principal neutralizing determinant of the HIV-1 envelope protein gp120

The model of spatial structure for the principal neutralizing determinant (PND) of the HIV-1 envelope protein gp120 is proposed in terms of two-dimensional nuclear Overhauser effect (NOE) spectroscopy data. To build the model, the NMR-based theoretical conformational analysis of synthetic PND peptides of length 40, 24, and 12 residues is carried out. The modeling of the molecular spatial structures is performed by a new approach to research of conformationally mobile peptides using the algorithms of the restrained molecular mechanics method developed earlier. The following major conclusions are made based on the analysis of the simulated peptide conformations: i) there is not unique PND structure in solution, ii) there are seven different PND structures each of which agrees with the experimental data and stereochemical criteria used in computing its spatial model, iii) the PND is characterized by irregular conformation containing a number of reverse turns, iv) all of the selected conformations are conserved in the Gly-Pro-Gly-Arg-Ala-Phe stretch, the most probable viral immunodominant epitope. These data allow to suppose that binding properties of this site are determined by the structural motif which forms the conformation of a double beta-turn and appears common for all hexapeptide structures.     

Spatial structure of the rp142 peptide containing the immunodominant epitope of the HIV-1 gp120 protein. A theoretical study]

A model of spatial structure of the synthetic peptide rp142 (24 amino acid residues) containing the immunodominant epitope of the HIV-1 protein gp120 in the region Gly-10-Phe-15 was constructed by the method of "constrained" molecular mechanics, which uses the algorithms of theoretical conformational analysis, based on NMR spectroscopy data. A comparative analysis of calculated conformations revealed that the spatial structure of rp142 in solution can be described by a family of conformations to which nine different structural clusters involving the sets of topologically close conformers correspond. It is shown that the main chain of the peptide forms irregular but "structured" conformations in which the main portion of amino acid residues is incorporated into beta-turns and helix-like fragments, while Pro-11 and Gly-12 form in some structures inverse gamma-turns, which rarely occur in protein-peptide molecules. It was found that the spatial packing of the Gly-10-Phe-15 hexapeptide in different clusters is realized at different internal rotation angles, to which topologically close structures correspond. It is assumed that this invariant structural element describes the "conformation of complex formation" that is complementary to the antigen-binding center of antibodies and is responsible for their binding to the peptide.     

Structural Analysis of the HIV-1 gp120 V3 Loop: Application to the HIV-Haiti Isolates

Abstract

The model describing the structure and conformational preferences of the HIV-Haiti V3 loop in the geometric spaces of Cartesian coordinates and dihedral angles was generated in terms of NMR spectroscopy data published in literature. To this end, the following successive steps were put into effect: (i) the NMR-based 3D structure for the HIV-Haiti V3 loop in water was built by computer modeling methods; (ii) the conformations of its irregular segments were analyzed and the secondary structure elements identified; and (iii) to reveal a common structural motifs in the HIV-Haiti V3 loop regardless of its environment variability, the simulated structure was collated with the one deciphered previously for the HIV-Haiti V3 loop in a water/trifluoroethanol (TFE) mixed solvent.

As a result, the HIV-Haiti V3 loop was found to offer the highly variable fragment of gp120 sensitive to its environment whose changes trigger the large-scale structural rearrangements, bringing in substantial altering the secondary and tertiary structures of this functionally important site of the virus envelope. In spite of this fact, over half of amino acid residues that reside, for the most part, in the functionally important regions of the gp120 protein and may present promising targets for AIDS drug researches, were shown to preserve their conformational states in the structures under review. In particular, the register of these amino acids holds Asn-25 that is critical for the virus binding with primary cell receptor CD4 as well as Arg-3 that is critical for utilization of CCR5 co-receptor and heparan sulfate proteoglycans. The conservative structural motif embracing one of the potential sites of the gp120 N-linked glycosylation was detected, which seems to be a promising target for the HIV-1 drug design.

The implications are discussed in conjunction with the literature data on the biological activity of the individual amino acids for the HIV-1 gp120 V3 loop.     

Conformational preferences of the HIV-1 principal neutralizing determinant

The model describing the conformational properties of the HIV-1 principal neutralizing determinant in the geometric space of dihedrals was generated in terms of NMR spectroscopy data published in literature. To gain an object in view, the following successive steps were put into effect: (i) the NMR-based local structures for the HIV(MN) V3 loop were determined in water and in a mixed water/trifluoroethanol (TFE) solvent (7:3), (ii) in either case, the conformations of its irregular segments were analyzed and the secondary structure elements identified, (iii) to appreciate the degree of conformational mobility of the stretch of interest, the simulated structures were compared with each other, (iv) to detect the amino acids retaining their conformations inside the diverse HIV-1 isolates, the structures computed were collated with the one derived previously for the V3 loop from Thailand isolate, and (v) as a matter of record, the structurally rigid residues, that may present the forward-looking targets for AIDS drug researches, were revealed. Summing up the principal results arising from these studies, the following conclusions were drawn: I. The HIV(MN) V3 loop offers the highly mobile fragment of gp120 sensitive to its environment whose changes trigger the large-scale structural reforms, bringing in substantial altering the secondary structure of this functionally important site of the virus envelope. II. In water, it exhibits extended site 1-14 separated by double beta-turn 15-20 with unordered region 21-35. III. Adding the TFE gives rise to destruction of the regular structure in the V3 loop N-terminal, stimulates the formation of 3(10)-helix in site 24-31, and affects also its central region 20-25 forming the HIV-1 immunogenic crown. IV. Regardless of statistically significant differences between local structures of the HIV(MN) V3 loop in water and in water/TFE solution, over one-third of residues keeps their conformational states; the register of these amino acids comprises Asn-25 critical for virus binding with primary cell receptor CD4 as well as Arg-3 critical for utilization of CCR5 coreceptor. V. There are no conserved structural motifs within the V3 loops from Minnesota and Thailand HIV-1 strains. However, perceptible portion of amino acids (more than 35%), including those appearing in the functionally important regions of gp120, holds the values of dihedral angles in which case. The implications are discussed in conjunction with the data on the experimental observations for the HIV-1 principal neutralizing determinant.     

Elicitation of neutralizing antibodies directed against CD4-induced epitope(s) using a CD4 mimetic cross-linked to a HIV-1 envelope glycoprotein

The identification of HIV-1 envelope glycoprotein (Env) structures that can generate broadly neutralizing antibodies (BNAbs) is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s) that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4) receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i) epitope(s) known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH), was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140) using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1) complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2(7312/V434M) and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s). These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s) here, and its potential role in vaccine application.     

Determining the invariant structure elements of the HIV-1 variable V3 loops: insight into the HIV-MN and HIV-Haiti isolates

The computer approaches that combined the 3D protein structure modeling with the mathematical statistics methods were used to compute the NMR-based 3D structures of the HIV-1 gp120 V3 loop for the HIV-MN and HIV-Haiti isolates in water as well as to compare their conformational characteristics with the purpose of determining the structure elements common for the two virus modifications. As a result, the variability of the amino acid sequence was found to stimulate the considerable structural rearrangements of the V3 loop. However, despite this fact, one functionally crucial stretch of V3 and a greater portion of its residues were shown to preserve the conformations in the viral strains of interest. To reveal the structural motifs and individual amino acids giving rise to the close conformations in the HIV-MN and HIV-Haiti V3 loops regardless of the sequence and environment variability, the simulated structures were collated with those deciphered previously in terms of NMR data in a water/trifluoroethanol mixed solvent. The structure elements and single residues of V3 residing in its biologically significant sites and keeping the conformations in all of the cases at question are considered to be the promising targets for anti-AIDS drugs studies. In this context, the structurally inflexible motifs of V3 presenting the weak units in the virus protection system may be utilized as the most convenient landing-places for molecular docking of the V3 loop and ligand structures followed by selecting chemical compounds suitable as a basis for the design of safe and effective antiviral agents.     

Indirect detection of an epitope-specific response to HIV-1 gp120 immunization in human subjects

A specific response of human serum neutralizing antibodies (nAb) to a conformational epitope as a result of vaccination of human subjects with the surface envelope glycoprotein (gp120) of HIV-1 has not previously been documented. Here, we used computational analysis to assess the epitope-specific responses of human subjects, which were immunized with recombinant gp120 immunogens in the VAX003 and VAX004 clinical trials. Our computational methodology--a variation of sieve analysis--compares the occurrence of specific nAb targeted conformational 3D epitopes on viruses from infected individuals who received vaccination to the occurrence of matched epitopes in the viruses infecting placebo subjects. We specifically studied seven crystallographically defined nAb targeted conformational epitopes in the V3 loop, an immunogenic region of gp120. Of the six epitopes present in the immunogens and targeted by known monoclonal neutralizing antibodies, only the one targeted by the anti-V3 nAb 2219 exhibited a significant reduction in occurrence in vaccinated subjects compared to the placebo group. This difference occurred only in the VAX003 Thailand cohort. No difference was seen between vaccinated and placebo groups for the occurrence of an epitope that was not present in the immunogen. Thus, it can be theorized that a specific 2219-like human neutralizing antibody immune response to AIDSVAX immunization occurred in the VAX003 cohort, and that this response protected subjects from a narrow subset of HIV-1 viruses circulating in Thailand in the 1990s and bearing the conformational epitope targeted by the neutralizing antibody 2219.     

Crystal structure of a human rhinovirus that displays part of the HIV-1 V3 loop and induces neutralizing antibodies against HIV-1

We report the 2.7 A resolution structure of a chimeric rhinovirus, MN-III-2, that displays part of the HIV-1 gp120 V3 loop and elicits HIV-neutralizing antibodies. The V3 loop insert is dominated by two type I beta turns. The structures of two adjacent tripeptides resemble those of analogous segments in three Fab/V3 loop peptide complexes. Although two of the three corresponding antibodies bind and neutralize MN-III-2 well, only one of the three can bind without significant rearrangement. These results suggest that the V3 loop insert: (1) can share some local conformational similarity to V3 loop sequences presented on different structural frameworks; (2) must be able to adopt multiple conformations, even in a relatively constrained environment; and (3) may mimic the conformational variability of the epitope on HIV-1, increasing the likelihood of eliciting appropriate neutralizing immune responses.     

Computational Prediction of Broadly Neutralizing HIV-1 Antibody Epitopes from Neutralization Activity Data

Broadly neutralizing monoclonal antibodies effective against the majority of circulating isolates of HIV-1 have been isolated from a small number of infected individuals. Definition of the conformational epitopes on the HIV spike to which these antibodies bind is of great value in defining targets for vaccine and drug design. Drawing on techniques from compressed sensing and information theory, we developed a computational methodology to predict key residues constituting the conformational epitopes on the viral spike from cross-clade neutralization activity data. Our approach does not require the availability of structural information for either the antibody or antigen. Predictions of the conformational epitopes of ten broadly neutralizing HIV-1 antibodies are shown to be in good agreement with new and existing experimental data. Our findings suggest that our approach offers a means to accelerate epitope identification for diverse pathogenic antigens.