Worldwide Distribution of HIV Type 1 Epitopes Recognized by Human Anti-V3 Monoclonal Antibodies

New York University School of Medicine, Departments of Pharmacology, Pathology and Environmental Medicine, New York, New York 10016, USA.
AIDS research and human retroviruses (Impact Factor: 2.33). 04/2009; 25(4):441-50. DOI: 10.1089/aid.2008.0188
Source: PubMed


Epitopes, also known as antigenic determinants, are small clusters of specific atoms within macromolecules that are recognized by the immune system. Such epitopes can be targeted with vaccines designed to protect against specific pathogens. The third variable loop (V3 loop) of the HIV-1 pathogen's gp120 surface envelope glycoprotein can be a highly sensitive neutralization target. We derived sequence motifs for the V3 loop epitopes recognized by the human monoclonal antibodies (mAbs) 447-52D and 2219. Searching the HIV database for the occurrence of each epitope motif in worldwide viruses and correcting the results based on published WHO epidemiology reveal that the 447-52D epitope we defined occurs in 13% of viruses infecting patients worldwide: 79% of subtype B viruses, 1% of subtype C viruses, and 7% of subtype A/AG sequences. In contrast, the epitope we characterized for human anti-V3 mAb 2219 is present in 30% of worldwide isolates but is evenly distributed across the known HIV-1 subtypes: 48% of subtype B strains, 40% of subtype C, and 18% of subtype A/AG. Various assays confirmed that the epitopes corresponding to these motifs, when expressed in the SF162 Env backbone, were sensitively and specifically neutralized by the respective mAbs. The method described here is capable of accurately determining the worldwide occurrence and subtype distribution of any crystallographically resolved HIV-1 epitope recognized by a neutralizing antibody, which could be useful for multivalent vaccine design. More importantly, these calculations demonstrate that globally relevant, structurally conserved epitopes are present in the sequence variable V3 loop.

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Available from: Arthur Joseph Nadas, Jun 05, 2015
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    • "However, scaling this approach up via high-throughput means to assess the thousands of circulating worldwide HIV-1 variants, the population of which are also constantly evolving, would not be feasible. The only computational alternative proposed to date is a heuristic Signature Motif Method (SMM) [13], [14]. This approach represents a neutralization epitope with a sequence pattern (signature motif). "
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    ABSTRACT: The extreme diversity of HIV-1 strains presents a formidable challenge for HIV-1 vaccine design. Although antibodies (Abs) can neutralize HIV-1 and potentially protect against infection, antibodies that target the immunogenic viral surface protein gp120 have widely variable and poorly predictable cross-strain reactivity. Here, we developed a novel computational approach, the Method of Dynamic Epitopes, for identification of neutralization epitopes targeted by anti-HIV-1 monoclonal antibodies (mAbs). Our data demonstrate that this approach, based purely on calculated energetics and 3D structural information, accurately predicts the presence of neutralization epitopes targeted by V3-specific mAbs 2219 and 447-52D in any HIV-1 strain. The method was used to calculate the range of conservation of these specific epitopes across all circulating HIV-1 viruses. Accurately identifying an Ab-targeted neutralization epitope in a virus by computational means enables easy prediction of the breadth of reactivity of specific mAbs across the diversity of thousands of different circulating HIV-1 variants and facilitates rational design and selection of immunogens mimicking specific mAb-targeted epitopes in a multivalent HIV-1 vaccine. The defined epitopes can also be used for the purpose of epitope-specific analyses of breakthrough sequences recorded in vaccine clinical trials. Thus, our study is a prototype for a valuable tool for rational HIV-1 vaccine design.
    PLoS ONE 02/2014; 9(2):e89987. DOI:10.1371/journal.pone.0089987 · 3.23 Impact Factor
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    • "In previous studies [19], [20], we identified seven overlapping signature motifs specific for seven interspersed conformational neutralization epitopes present in the V3 loop crown. These motifs were defined as the critical residues recognized by various broadly neutralizing human anti-V3 monoclonal antibodies, and allowed us to identify the presence or absence of specific conformational epitopes in any HIV-1 virus [19], [20]. In the current study, we used this novel capability to identify the presence or absence of these epitopes in vaccine immunogens and in break-through viruses infecting vaccine and placebo recipients in the VAX003 and VAX004 Phase III clinical trials [1], [2]. "
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    ABSTRACT: 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.
    PLoS ONE 11/2011; 6(11):e27279. DOI:10.1371/journal.pone.0027279 · 3.23 Impact Factor
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    • "Briefly, a signature motif for an epitope is generated via examination of sequence-specific atomic contacts in a co-crystal structure between the monoclonal antibody (mAb) and a bound peptide's side chain atoms (Examples for mAbs 3074, 2557 and 268-D are shown in Figure 1). Only contacts in which the side-chain is largely buried in a pocket on the mAb molecular surface are included in the motif, as these were shown in the previous study [30] to be neutralization-specific. Any mAb contacts with peptide main-chain atoms are not included in the motif, as these are not sequence (side-chain) specific, and viral escape mutations that change the side chain will not necessarily alter the backbone or the mAb interaction. "
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    ABSTRACT: Although the sequence variable loops of the human immunodeficiency virus' (HIV-1) surface envelope glycoprotein (gp120) can exhibit good immunogenicity, characterizing conserved (invariant) cross-strain neutralization epitopes within these loops has proven difficult. We recently developed a method to derive sensitive and specific signature motifs for the three-dimensional (3D) shapes of the HIV-1 neutralization epitopes in the third variable (V3) loop of gp120 that are recognized by human monoclonal antibodies (mAbs). We used the signature motif method to estimate the conservation of these epitopes across circulating worldwide HIV-1 strains. The epitope targeted by the anti-V3 loop neutralizing mAb 3074 is present in 87% of circulating strains, distributed nearly evenly among all subtypes. The results for other anti-V3 Abs are: 3791, present in 63% of primarily non-B subtypes; 2219, present in 56% of strains across all subtypes; 2557, present in 52% across all subtypes; 447-52D, present in 11% of primarily subtype B strains; 537-10D, present in 9% of primarily subtype B strains; and 268-D, present in 5% of primarily subtype B strains. The estimates correlate with in vitro tests of these mAbs against diverse viral panels. The mAb 3074 thus targets an epitope that is nearly completely conserved among circulating HIV-1 strains, demonstrating the presence of an invariant structure hidden in the dynamic and sequence-variable V3 loop in gp120. Since some variable loop regions are naturally immunogenic, designing immunogens to mimic their conserved epitopes may be a promising vaccine discovery approach. Our results suggest one way to quantify and compare the magnitude of the conservation.
    PLoS ONE 12/2010; 5(12):e15994. DOI:10.1371/journal.pone.0015994 · 3.23 Impact Factor
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