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Book ChapterDOI

Short Oligopeptide T-Cell Epitopes in HIV-1/AIDS Vaccine Development: Current Status, Design, Promises and Challenges

TL;DR: The structural resolution of gp120 trimer spike pre-fusion is highly promising for recombinant vaccine development, however, the production of the native spike trimer complex is a biotechnological challenge for protein engineering, refolding and assembly.
Abstract: The development of a HIV-1/AIDS vaccine is a technological challenge over the last two decades due to HIV-1 viral diversity, sequence similarity between human and HIV proteins and HIV-1/human host molecular mimicry. The challenges and complexities associated with an ENV-gp120 subunit-based recombinant protein vaccine are discussed in detail for over a decade. Clinical trials using RV144 (Env-gp120, Gag and Pro) candidate vaccine are marginally promising yet unsuccessful. This is attributed to viral mutation, protein size, protein type (unstable membrane protein) and the native structure of glycosylated gp160 as a trimer complex spike on the envelope (ENV). The structural resolution of gp120 trimer spike pre-fusion is highly promising for recombinant vaccine development. However, the production of the native spike trimer complex is a biotechnological challenge for protein engineering, refolding and assembly. Hence, there is a need for the development of an alternative vaccine type for HIV-1/AIDS.
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Journal ArticleDOI
TL;DR: This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk and offer insight for future research.
Abstract: In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], −4.0 to 47.9; P = 0.08). In the perprotocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, −13.3 to 51.9; P = 0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P = 0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. Conclusions This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

2,960 citations

Journal ArticleDOI
23 Oct 2014-Nature
TL;DR: The structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22 is reported, revealing the pre-fusion conformation of gp41, rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition.
Abstract: The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation. A crystal structure of the human immunodeficiency virus Env trimer, used by the virus to infect cells, is determined here; the new structure, which shows the pre-fusion form of Env, increases our understanding of the fusion mechanism and of how the conformation of Env allows the virus to evade the immune response. Peter Kwong and colleagues provide a new crystal structure of the human immunodeficiency virus type 1 (HIV-1) Env trimer, part of the type I fusion machine that facilitates virus entry into cells by interacting with host cellular receptors and fusing membranes of virus and host cell. The Env trimer consists of three gp120 and three gp41 subunits. The structure, at 3.5 A resolution, shows the pre-fusion form of Env and allows the conformation of the gp41 subunits to be resolved, thereby increasing our understanding of how the trimer functions to enable fusion and how it evades recognition by the immune response. This evasion is, to a large degree, responsible for the difficulty in developing an effective HIV-1 vaccine.

692 citations

Journal ArticleDOI
TL;DR: The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class, as well as an extended class, for which V1V2-directed bNAbs form an 'extended class'.
Abstract: Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. The ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.

152 citations

Journal ArticleDOI
TL;DR: Emerging data from preclinical trials reinforce the need for additional insight into virus-host biology in order to facilitate the development of a successful vaccine.

137 citations

Journal ArticleDOI
TL;DR: The design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans are described.

99 citations