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Book ChapterDOI

HIV-1 Envelope (ENV) GP160 Trimer Protein Complex SPIKE as a Recombinant Macromolecular Assembly Vaccine Component Candidate: Current Opinion

TL;DR: The production of a native conformation of the HIV-1 ENV GP160 trimer SPIKE with appropriate glycosylation taking into consideration about 39,000 variants of known GP160 sequences among known subtypes is found to be nontrivial.
Abstract: The development of an HIV-1/AIDS vaccine has posed great challenges over the last two decades to the international scientific community. The synthesis of a viable vaccine component has gained momentum in recent years after several learning stories with partial success. The moderate efficacy showed by RV144 (ENV-gp120, Gag and Pro) vaccine (Thai trial vaccine) in clinical trials provided impetus to the study during the last decade. The technological challenge in the production of the viral spike as a viable vaccine component is realized since the conclusion of the Thai trial (2009). The results from the NIAID-sponsored South African HVTN 702 (ALVAC-HIV + subtype C gp120/MF59 2700) trial are awaited. The HIV-1 envelope spike [ENV GP160 trimer complex] is being exploited as a promising vaccine candidate in recent years. A number of knowledge points on the viral spike are now available using data derived from several disciplines of biotechnology. The production of a native conformation of the HIV-1 ENV GP160 trimer SPIKE with appropriate glycosylation taking into consideration about 39,000 variants of known GP160 sequences among known subtypes (as available at the LANL database) is found to be nontrivial. The known HIV-1 ENV GP160 trimer SPIKE electron microscopy structure at 4.19 A resolution shows nine interfaces with three different types. Their characteristic features are interesting towards the development of a stable yet effective trimer complex. The GP41-GP41 and GP41-GP120 interfaces are characteristics of equal polar to non-polar residues, and the GP120-GP120 interfaces are predominantly polar in nature. These data find application in the development of an immunologically viable vaccine component.
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Journal ArticleDOI
TL;DR: A series of novel thiazolo[3,2-b][1,2,4]-triazoles 3a-n has been synthesized and evaluated in vitro as potential antiproliferative and docking analyses revealed the highest affinities for compounds 3b-d which induced p53 activity in MCF-7 cancer cells.

22 citations

Journal ArticleDOI
TL;DR: The previous finding stating that small protein-protein interfaces rich in electrostatics holds true in case of GP41 whereas not with GP120 protein interfaces holds true.
Abstract: The Human Immunodeficiency Virus (HIV-1) type 1 viral protein is a life threatening virus causing HIV/AIDS in infected humans. The HIV-1 envelope (ENV) trimer glycoprotein GP160 (GP120-GP41) is gaining attention in recent years as a potential vaccine candidate for HIV-1/AIDS. However, the sequence variation and charge polarity at the interacting sites across clades is a shortcoming faced in the development of an effective HIV-1 vaccine. We analyzed the interfaces in terms of its interface area, interface size, and interface energies (van der Waals, hydrogen bonds, and electrostatics). The interfaces were divided as dominant (≥60%) and subdominant (<60%) based on van der Waals contribution to total energies. 88% of GP120 and 74% of GP41 interfaces are highly pronounced with van der Waals energy having large interfaces with interface size (98±65 (GP120) and 73±65 (GP41)) and interface area (882±1166A2 (GP120) and 921±1288A2 (GP41)). Nevertheless, 12% of GP120 and 26% of GP41 interfaces have subdominant van der Waals energies having small interfaces with interface size (58±20 (GP120) and 27±9 (GP41)) and interface area (581±1605A2 (GP120) and 483±896A2 (GP41)). It was interesting to observe GP41 small interfaces with subdominant van der Waals are stabilized by electrostatics (r2=0.63) without hydrogen bonds (r2=0). However, GP120 small interfaces were found to have two fold more hydrogen bonds (r2=0.59) than electrostatics (r2=0.20). Therefore, our previous finding stating that small protein-protein interfaces rich in electrostatics holds true in case of GP41 whereas not with GP120 protein interfaces.
References
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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
TL;DR: This review examines protein complexes in the Brookhaven Protein Databank to gain a better understanding of the principles governing the interactions involved in protein-protein recognition.
Abstract: This review examines protein complexes in the Brookhaven Protein Databank to gain a better understanding of the principles governing the interactions involved in protein-protein recognition. The factors that influence the formation of protein-protein complexes are explored in four different types of protein-protein complexes--homodimeric proteins, heterodimeric proteins, enzyme-inhibitor complexes, and antibody-protein complexes. The comparison between the complexes highlights differences that reflect their biological roles.

2,515 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: Fast, memory‐efficient and robust execution make this software attractive for applications both in computationally expensive energy minimization algorithms, such as docking or molecular dynamics simulations, and in stand‐alone surface area and curvature calculations.
Abstract: New computer programs, SurfRace and FastSurf, perform fast calculations of the solvent accessible and molecular (solvent excluded) surface areas of macromolecules. Program SurfRace also calculates the areas of cavities inaccessible from the outside. We introduce the definition of average curvature of molecular surface and calculate average molecular surface curvatures for each atom in a structure. All surface area and curvature calculations are analytic and therefore yield exact values of these quantities. High calculation speed of this software is achieved primarily by avoiding computationally expensive mathematical procedures wherever possible and by efficient handling of surface data structures. The programs are written initially in the language C for PCs running Windows 2000/98/NT, but their code is portable to other platforms with only minor changes in input-output procedures. The algorithm is robust and does not ignore either multiplicity or degeneracy of atomic overlaps. Fast, memory-efficient and robust execution make this software attractive for applications both in computationally expensive energy minimization algorithms, such as docking or molecular dynamics simulations, and in stand-alone surface area and curvature calculations.

383 citations

Journal ArticleDOI
TL;DR: These Env trimers when used as immunogens, have led to the first vaccine‐induced neutralizing antibodies for structural and functional analyses and have stimulated further design and stabilization of EnV trimers as well as other platforms to generate trimers that now span multiple subtypes.
Abstract: Structure determination of the HIV-1 envelope glycoprotein (Env) presented a number of challenges, but several high-resolution structures have now become available. In 2013, cryo-EM and x-ray structures of soluble, cleaved SOSIP Env trimers from the clade A BG505 strain provided the first glimpses into the Env trimer fold as well as more the variable regions. A recent cryo-EM structure of a native full-length trimer without any stabilizing mutations had the same core structure, but revealed new insights and features. A more comprehensive and higher resolution understanding of the glycan shield has also emerged, enabling a more complete representation of the Env glycoprotein structure. Complexes of Env trimers with broadly neutralizing antibodies have surprisingly illustrated that most of the Env surface can be targeted in natural infection and that the neutralizing epitopes are almost all composed of both peptide and glycan components. These structures have also provided further evidence of the inherent plasticity of Env and how antibodies can exploit this flexibility by perturbing or even stabilizing the trimer to facilitate neutralization. These breakthroughs have stimulated further design and stabilization of Env trimers as well as other platforms to generate trimers that now span multiple subtypes. These Env trimers when used as immunogens, have led to the first vaccine-induced neutralizing antibodies for structural and functional analyses.

222 citations

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