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Journal of Chemical Information and... Jan 2022The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of...
The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied. Accelerated molecular dynamics (aMD) and ab initio hybrid molecular dynamics have been combined to determine the most persistent interactions between the most populated conformations of the antibody-antigen complex under physiological conditions. The results show the most persistent receptor-binding mapping in the conformations of the antibody-antigen interface in solution. The binding-free-energy decomposition reveals a small enhancement in the contribution played by the CDR-H3 region to the b12-gp120 interface compared to the crystal structure.
Topics: Amino Acid Sequence; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunoglobulin G
PubMed: 34971312
DOI: 10.1021/acs.jcim.1c01143 -
Archives of Virology Jan 2021This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the... (Review)
Review
This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the inability of vaccinologists to develop an effective HIV vaccine. The strong goal-directed intentionality inherent in the concept of design together with excessive confidence in the power of rational thinking convinced investigators that the accumulated structural knowledge on HIV epitopes, derived from crystallographic studies of complexes of neutralizing antibodies bound to HIV Env epitopes, would allow them to rationally design complementary immunogens capable of inducing anti-HIV protective antibodies. This strategy failed because it was not appreciated that the structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not represent structures present in the free disordered molecules before they had interacted. In addition, reductionist thinking led investigators to accept that biology could be reduced to chemistry, and this made them neglect the fundamental difference between chemical antigenicity and biological immunogenicity. As a result, they did not investigate which inherent constituents of immune systems controlled the induction of protective antibodies and focused instead only on the steric complementarity that exists between bound epitopes and paratopes.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Epitopes; HIV; HIV Antibodies; Humans
PubMed: 33251565
DOI: 10.1007/s00705-020-04884-0 -
AIDS Reviews 2015Broadly neutralizing antibodies represent the major protective mechanism of vaccines targeting pathogenic microbes in humans and animals. For HIV, broadly neutralizing... (Review)
Review
Broadly neutralizing antibodies represent the major protective mechanism of vaccines targeting pathogenic microbes in humans and animals. For HIV, broadly neutralizing antibodies have also been shown to be protective in experimental animal models. However, despite the identification of a respectable number of broadly neutralizing antibodies from chronically infected HIV-positive persons in recent years, attempts to induce such antibodies by vaccines have generally failed over the last decades. Though unsuccessful in view of achieving a protective vaccine against HIV, many of these studies have contributed significantly to the understanding of the generation of broadly neutralizing antibodies against HIV-1 as well as to the vulnerable sites they target on the surface of the virus. Here we review the most important features of patient-derived broadly neutralizing antibodies, the long and complex B-cell maturation pathways required for their production, and the resulting consequences for vaccine development. We further address characteristics of the epitopes targeted by broadly neutralizing antibodies on the virus surface as well as mechanisms of viral escape. Taken together, the identification of vaccine candidates able to induce broadly neutralizing antibodies against HIV-1 is the major challenge in HIV vaccine development. Mutual coevolution of rationally designed HIV vaccine candidates, with affinity maturation pathways of antibodies they induce upon vaccination, may best mimic the natural situation of chronically HIV-infected patients who are able to generate broadly neutralizing antibodies.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; B-Lymphocytes; Epitopes, B-Lymphocyte; Genetic Variation; HIV Antibodies; HIV Infections; HIV-1; Humans; Immune Evasion
PubMed: 26035168
DOI: No ID Found -
Science (New York, N.Y.) Dec 2022Clinical trial shows that an HIV vaccine can elicit rare antibodies, but there is more to do.
Clinical trial shows that an HIV vaccine can elicit rare antibodies, but there is more to do.
Topics: Humans; AIDS Vaccines; Broadly Neutralizing Antibodies; Genes, Immunoglobulin; Germ Cells; HIV Antibodies; HIV-1; Immunoglobulins; Vaccination; Randomized Controlled Trials as Topic
PubMed: 36454831
DOI: 10.1126/science.adf3722 -
Frontiers in Cellular and Infection... 2022The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and...
The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and catalyze rational vaccine development. Traditional mAb discovery is a costly and labor-intensive process, although recent advances in single-cell genomics using emulsion microfluidics allow simultaneous processing of thousands of individual cells. Here we present a streamlined method for isolation and analysis of large numbers of antigen-specific B cells, including next generation antigen barcoding and an integrated computational framework for B cell multi-omics. We demonstrate the power of this approach by recovering thousands of antigen-specific mAbs, including the efficient isolation of extremely rare precursors of VRC01-class and IOMA-class broadly neutralizing HIV mAbs.
Topics: Antibodies, Neutralizing; B-Lymphocytes; HIV Antibodies; Antigens; Antibodies, Monoclonal; HIV-1
PubMed: 36968243
DOI: 10.3389/fcimb.2022.962945 -
Expert Review of Vaccines Aug 2021: An efficacious vaccine for HIV-1 has been sought for over 30 years to eliminate the virus from the human population. Many challenges have occurred in the attempt to... (Review)
Review
: An efficacious vaccine for HIV-1 has been sought for over 30 years to eliminate the virus from the human population. Many challenges have occurred in the attempt to produce a successful immunogen, mainly caused by the basic biology of the virus. Immunogens have been developed focusing on inducing one or more of the following types of immune responses; neutralizing antibodies, non-neutralizing antibodies, and T-cell mediated responses. One way to better present and develop an immunogen for HIV-1 is through the use of nanotechnology and nanoparticles.: This article gives a basic overview of the HIV-1 vaccine field, as well as nanotechnology, specifically nanovaccines. It then covers the application of nanovaccines made from biological macromolecules to HIV-1 vaccine development for neutralizing antibodies, non-neutralizing antibodies, and T-cell-mediated responses.: Nanovaccines are an area that is ripe for further exploration in HIV-1 vaccine field. Not only are nanovaccines capable of carrying and presenting antigens in native-like conformations, but they have also repeatedly been shown to increase immunogenicity over recombinant antigens alone. Only through further research can the true role of nanovaccines in the development of an efficacious HIV-1 vaccine be established.
Topics: AIDS Vaccines; Antibodies, Neutralizing; HIV Antibodies; HIV-1; Humans; Vaccine Development; Vaccines
PubMed: 34184607
DOI: 10.1080/14760584.2021.1945448 -
MMW Fortschritte Der Medizin May 2022
Topics: COVID-19; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 35513674
DOI: 10.1007/s15006-022-1134-2 -
Advances in Immunology 2019Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate... (Review)
Review
Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env glycans are derived from the host and present a formidable challenge for host anti-glycan antibody induction. Anti-glycan antibody induction is challenging because anti-HIV-1 glycan antibodies should recognize Env antigen while not acquiring autoreactivity. Thus, the glycan network on HIV-1 Env is referred to as the glycan shield. Despite the challenges presented by immune recognition of host-derived glycans, neutralizing antibodies capable of binding the glycans on HIV-1 Env can be generated by the host immune system in the setting of HIV-1 infection. In particular, a cluster of high mannose glycans, including an N-linked glycan at position 332, form the high mannose patch and are targeted by a variety of broadly neutralizing antibodies. These high mannose patch-directed HIV-1 antibodies can be categorized into distinct categories based on their antibody paratope structure, neutralization activity, and glycan and peptide reactivity. Below we will compare and contrast each of these classes of HIV-1 glycan-dependent antibodies and describe vaccine design efforts to elicit each of these antibody types.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibody Formation; Broadly Neutralizing Antibodies; Epitopes; Glycosylation; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunogenicity, Vaccine; Mannose; Peptide Fragments; Polysaccharides
PubMed: 31607367
DOI: 10.1016/bs.ai.2019.08.002 -
AIDS (London, England) Jul 2017: Passive immunization, the transfer of antibodies to a nonimmune individual to provide immunological protection, has been used for over 100 years to prevent and treat... (Review)
Review
: Passive immunization, the transfer of antibodies to a nonimmune individual to provide immunological protection, has been used for over 100 years to prevent and treat human infectious diseases. The introduction of techniques to produce human mAbs has revolutionized the field, and a large number of human mAbs have been licensed for the treatment of cancer, autoimmune and inflammatory diseases. With the recent discovery and production of highly potent broadly neutralizing and other multifunctional antibodies to HIV, mAbs are now being considered for HIV therapy and prophylaxis. In this review, we briefly present recent advances in the anti-HIV mAb field and outline strategies for the selection, engineering and production of human mAbs, including the modification of their structure for optimized stability and function. We also describe results from nonhuman primate studies and phase 1 clinical trials that have tested the safety, tolerability, pharmacokinetics, and efficacy of mAb-based HIV prevention strategies, and discuss the future of parenteral and topical mAb administration for the prevention of HIV transmission.
Topics: Administration, Topical; Animals; Antibodies, Monoclonal; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization, Passive; Pre-Exposure Prophylaxis; Rectum; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Treatment Outcome; Vagina
PubMed: 28463876
DOI: 10.1097/QAD.0000000000001521 -
MMW Fortschritte Der Medizin Jun 2015
Review
Topics: AIDS Vaccines; Animals; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; Humans; Immunization, Passive; Immunotherapy; Prospective Studies; Viral Load
PubMed: 26048121
DOI: 10.1007/s15006-015-3167-2