Article

Quantitative Assessment of HIV-1 Neutralization Epitope Masking

Department of Pharmacology, New York University School of Medicine, 550 First Avenue MSB 497, New York, NY 10016, USA.
Vaccine (Impact Factor: 3.49). 09/2011; 29(39):6736-41. DOI: 10.1016/j.vaccine.2010.12.052
Source: PubMed

ABSTRACT Despite the frequent observation of masking of HIV-1 neutralization epitopes, its extent has not been previously systematically assessed either for multiple epitopes presented by individual viruses or for individual epitopes across multiple viral strains. Using a recently developed method to identify amino acid sequence motifs required for recognition by HIV-1-neutralizing monoclonal antibodies (mAbs), we visualized the patterns of masking of specific epitopes targeted by mAbs in a diverse panel of HIV-1 isolates. We also calculated a specific masking intensity score for each virus based on the observed neutralization activity of mAbs against the epitopes in the virus. Finally, we combined these data with estimates of the conservation of each mAb-targeted epitope in circulating HIV-1 strains to estimate the effective neutralization potential (E(N)) for each mAb. Focusing on the V3 loop of gp120 as a prototype neutralization domain, we found that the V3 loop epitope targeted by mAb 2219 is one of the least masked mAbs and it has the highest E(N). Interestingly, although the V3 loop epitope targeted by mAb 3074 is present in over 87% of all viruses, it is 82.2% masked, so its E(N) is lower than that for mAb 2219. Notably, 50% of the viruses that mAb 3074 is able to neutralize are classified as subtype C viruses, while 70% or more of the viruses neutralized by mAbs 2219, 2557 or 447-52D are classified as subtype B. Thus, neutralization epitopes (in this case, in the V3 loop) have differential patterns of masking and also display distinct patterns of distribution among circulating HIV-1 viruses. Both factors combine to contribute to the practical vaccine value of any single epitope/mAb. Here we have developed a quantitative score for this value. These results have important implications for rational design of vaccines designed to induce neutralizing Abs by revealing epitopes that are minimally masked and maximally reactive with neutralizing Abs.

0 Followers
 · 
121 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This review describes the structure-based reverse vaccinology approach aimed at developing vaccine immunogens capable of inducing antibodies that broadly neutralize HIV-1. Some basic principles of protein immunochemistry are reviewed and the implications of the extensive polyspecificity of antibodies for vaccine development are underlined. Although it is natural for investigators to want to know the cause of an effective immunological intervention, the classic notion of causality is shown to have little explanatory value for a system as complex as the immune system, where any observed effect always results from many interactions between a large number of components. Causal explanations are reductive because a single factor is singled out for attention and given undue explanatory weight on its own. Other examples of the negative impact of reductionist thinking on HIV vaccine development are discussed. These include (1) the failure to distinguish between the chemical nature of antigenicity and the biological nature of immunogenicity, (2) the belief that when an HIV-1 epitope is reconstructed by rational design to better fit a neutralizing monoclonal antibody (nMab), this will produce an immunogen able to elicit Abs with the same neutralizing capacity as the Ab used as template for designing the antigen, and (3) the belief that protection against infection can be analyzed at the level of individual molecular interactions although it has meaning only at the level of an entire organism. The numerous unsuccessful strategies that have been used to design HIV-1 vaccine immunogens are described and it is suggested that the convergence of so many negative experimental results justifies the conclusion that reverse vaccinology is unlikely to lead to the development of a preventive HIV-1 vaccine. Immune correlates of protection in vaccines have not yet been identified because this will become feasible only retrospectively once an effective vaccine exists. The finding that extensive antibody affinity maturation is needed to obtain mature anti-HIV-1 Abs endowed with a broad neutralizing capacity explains why antigens designed to fit matured Mabs are not effective vaccine immunogens since these are administered to naive recipients who possess only B-cell receptors corresponding to the germline version of the matured Abs.
    Frontiers in Immunology 07/2012; 3:194. DOI:10.3389/fimmu.2012.00194
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    AIDS research and human retroviruses 04/2009; 25(4):441-50. DOI:10.1089/aid.2008.0188 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of a safe, effective and globally affordable HIV vaccine offers the best hope for the future control of the HIV-1 pandemic. Since 1987, scores of candidate HIV-1 vaccines have been developed which elicited varying degrees of protective responses in nonhuman primate models, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost combinations. Four of these candidate vaccines have been tested for efficacy in human volunteers, but, to the exception of the recent RV144 Phase III trial in Thailand, which elicited a modest but statistically significant level of protection against infection, none has shown efficacy in preventing HIV-1 infection or in controlling virus replication and delaying progression of disease in humans. Protection against infection was observed in the RV144 trial, but intensive research is needed to try to understand the protective immune mechanisms at stake. Building-up on the results of the RV144 trial and deciphering what possibly are the immune correlates of protection are the top research priorities of the moment, which will certainly accelerate the development of an highly effective vaccine that could be used in conjunction with other HIV prevention and treatment strategies. This article reviews the state of the art of HIV vaccine development and discusses the formidable scientific challenges met in this endeavor, in the context of a better understanding of the immunopathogenesis of the disease.
    Vaccine 06/2011; 29(37):6191-218. DOI:10.1016/j.vaccine.2011.06.085 · 3.49 Impact Factor

Preview

Download
0 Downloads
Available from