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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 -
Bioinformatics (Oxford, England) Sep 2022Knowing the sensitivity of a viral strain versus a monoclonal antibody is of interest for HIV vaccine development and therapy. The HIV strains vary in their resistance...
MOTIVATION
Knowing the sensitivity of a viral strain versus a monoclonal antibody is of interest for HIV vaccine development and therapy. The HIV strains vary in their resistance to antibodies, and the accurate prediction of virus-antibody sensitivity can be used to find potent antibody combinations that broadly neutralize multiple and diverse HIV strains. Sensitivity prediction can be combined with other methods such as generative algorithms to design novel antibodies in silico or with feature selection to uncover the sites of interest in the sequence. However, these tools are limited in the absence of in silico accurate prediction methods.
RESULTS
Our method leverages the CATNAP dataset, probably the most comprehensive collection of HIV-antibodies assays, and predicts the antibody-virus sensitivity in the form of binary classification. The methods proposed by others focus primarily on analyzing the virus sequences. However, our article demonstrates the advantages gained by modeling the antibody-virus sensitivity as a function of both virus and antibody sequences. The input is formed by the virus envelope and the antibody variable region aminoacid sequences. No structural features are required, which makes our system very practical, given that sequence data is more common than structures. We compare with two other state-of-the-art methods that leverage the same dataset and use sequence data only. Our approach, based on neuronal networks and transfer learning, measures increased predictive performance as measured on a set of 31 specific broadly neutralizing antibodies.
AVAILABILITY AND IMPLEMENTATION
https://github.com/vlad-danaila/deep_hiv_ab_pred/tree/fc-att-fix.
Topics: Humans; HIV Antibodies; Antibodies, Neutralizing; Antibodies, Monoclonal; HIV-1; Deep Learning; HIV Infections
PubMed: 35876860
DOI: 10.1093/bioinformatics/btac530 -
Proceedings of the National Academy of... Mar 2023Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)] that...
Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.
Topics: Humans; HIV-1; HIV Seropositivity; HIV Infections; Antibody-Dependent Cell Cytotoxicity; HIV Envelope Protein gp120; CD4 Antigens; HIV Antibodies
PubMed: 36961924
DOI: 10.1073/pnas.2222073120 -
Current Opinion in HIV and AIDS May 2015This review highlights recent developments in HIV-1 antibody engineering and discusses the effects of increased polyreactivity on serum half-lives of engineered... (Review)
Review
PURPOSE OF REVIEW
This review highlights recent developments in HIV-1 antibody engineering and discusses the effects of increased polyreactivity on serum half-lives of engineered antibodies.
RECENT FINDINGS
Recent studies have uncovered a wealth of information about the relationship between the sequences and efficacies of anti-HIV-1 antibodies through a combination of bioinformatics, structural characterization and in vivo studies. This knowledge has stimulated efforts to enhance antibody breadth and potency for therapeutic use. Although some engineered antibodies have shown increased polyreactivity and short half-lives, promising efforts are circumventing these problems.
SUMMARY
Antibodies are desirable as therapeutics due to their ability to recognize targets with both specificity and high affinity. Furthermore, the ability of antibodies to stimulate Fc-mediated effector functions can increase their utility. Thus, mAbs have become central to strategies for the treatment of various diseases. Using both targeted and library-based approaches, antibodies can be engineered to improve their therapeutic properties. This article will discuss recent antibody engineering efforts to improve the breadth and potency of anti-HIV-1 antibodies. The polyreactivity of engineered HIV-1 bNAbs and the effect on serum half-life will be explored along with strategies to overcome problems introduced by engineering antibodies. Finally, advances in creating bispecific anti-HIV-1 reagents are discussed.
Topics: Animals; Antibodies, Bispecific; Binding Sites; HIV Antibodies; Humans; Mice; Models, Molecular; Protein Engineering
PubMed: 25760931
DOI: 10.1097/COH.0000000000000148 -
Artificial Intelligence in Medicine Dec 2022Machine learning algorithms play an essential role in bioinformatics and allow exploring the vast and noisy biological data in unrivaled ways. This paper is a systematic... (Review)
Review
Machine learning algorithms play an essential role in bioinformatics and allow exploring the vast and noisy biological data in unrivaled ways. This paper is a systematic review of the applications of machine learning in the study of HIV neutralizing antibodies. This significant and vast research domain can pave the way to novel treatments and to a vaccine. We selected the relevant papers by investigating the available literature from the Web of Science and PubMed databases in the last decade. The computational methods are applied in neutralization potency prediction, neutralization span prediction against multiple viral strains, antibody-virus binding sites detection, enhanced antibodies design, and the study of the antibody-induced immune response. These methods are viewed from multiple angles spanning data processing, model description, feature selection, evaluation, and sometimes paper comparisons. The algorithms are diverse and include supervised, unsupervised, and generative types. Both classical machine learning and modern deep learning were taken into account. The review ends with our ideas regarding future research directions and challenges.
Topics: Humans; HIV Antibodies; Machine Learning; HIV-1; Antibodies, Neutralizing; HIV Infections
PubMed: 36462896
DOI: 10.1016/j.artmed.2022.102429 -
Journal of Virology Jan 2015It is generally acknowledged that human broadly neutralizing antibodies (bNAbs) capable of neutralizing multiple HIV-1 clades are often polyreactive or autoreactive....
UNLABELLED
It is generally acknowledged that human broadly neutralizing antibodies (bNAbs) capable of neutralizing multiple HIV-1 clades are often polyreactive or autoreactive. Whereas polyreactivity or autoreactivity has been proposed to be crucial for neutralization breadth, no systematic, quantitative study of self-reactivity among nonneutralizing HIV-1 Abs (nNAbs) has been performed to determine whether poly- or autoreactivity in bNAbs is a consequence of chronic antigen (Ag) exposure and/or inflammation or a fundamental property of neutralization. Here, we use protein microarrays to assess binding to >9,400 human proteins and find that as a class, bNAbs are significantly more poly- and autoreactive than nNAbs. The poly- and autoreactive property is therefore not due to the infection milieu but rather is associated with neutralization. Our observations are consistent with a role of heteroligation for HIV-1 neutralization and/or structural mimicry of host Ags by conserved HIV-1 neutralization sites. Although bNAbs are more mutated than nNAbs as a group, V(D)J mutation per se does not correlate with poly- and autoreactivity. Infrequent poly- or autoreactivity among nNAbs implies that their dominance in humoral responses is due to the absence of negative control by immune regulation. Interestingly, four of nine bNAbs specific for the HIV-1 CD4 binding site (CD4bs) (VRC01, VRC02, CH106, and CH103) bind human ubiquitin ligase E3A (UBE3A), and UBE3A protein competitively inhibits gp120 binding to the VRC01 bNAb. Among these four bNAbs, avidity for UBE3A was correlated with neutralization breadth. Identification of UBE3A as a self-antigen recognized by CD4bs bNAbs offers a mechanism for the rarity of this bNAb class.
IMPORTANCE
Eliciting bNAbs is key for HIV-1 vaccines; most Abs elicited by HIV-1 infection or immunization, however, are strain specific or nonneutralizing, and unsuited for protection. Here, we compare the specificities of bNAbs and nNAbs to demonstrate that bNAbs are significantly more poly- and autoreactive than nNAbs. The strong association of poly- and autoreactivity with bNAbs, but not nNAbs from infected patients, indicates that the infection milieu, chronic inflammation and Ag exposure, CD4 T-cell depletion, etc., alone does not cause poly- and autoreactivity. Instead, these properties are fundamentally linked to neutralization breadth, either by the requirement for heteroligation or the consequence of host mimicry by HIV-1. Indeed, we show that human UBE3A shares an epitope(s) with HIV-1 envelope recognized by four CD4bs bNAbs. The poly- and autoreactivity of bNAbs surely contribute to the rarity of membrane-proximal external region (MPER) and CD4bs bNAbs and identify a roadblock that must be overcome to induce protective vaccines.
Topics: Autoantibodies; HIV Antibodies; HIV-1; Humans; Microarray Analysis; Protein Array Analysis; Protein Binding
PubMed: 25355869
DOI: 10.1128/JVI.02378-14 -
Viruses Sep 2017Human immunodeficiency virus (HIV) is a causative agent of acquired immune deficiency syndrome (AIDS). Highly active antiretroviral therapy (HAART) can slow down the... (Review)
Review
Human immunodeficiency virus (HIV) is a causative agent of acquired immune deficiency syndrome (AIDS). Highly active antiretroviral therapy (HAART) can slow down the replication of HIV-1, leading to an improvement in the survival of HIV-1-infected patients. However, drug toxicities and poor drug administration has led to the emergence of a drug-resistant strain. HIV-1 immunotherapy has been continuously developed, but antibody therapy and HIV vaccines take time to improve its efficiency and have limitations. HIV-1-specific chimeric antigen receptor (CAR)-based immunotherapy founded on neutralizing antibodies is now being developed. In HIV-1 therapy, anti-HIV chimeric antigen receptors showed promising data in the suppression of HIV-1 replication; however, autologous transfusion is still a problem. This has led to the development of effective peptides and proteins for an alternative HIV-1 treatment. In this paper, we provide a comprehensive review of potent anti-HIV-1 peptides and proteins that reveal promising therapeutic activities. The inhibitory mechanisms of each therapeutic molecule in the different stages of the HIV-1 life cycle will be discussed herein.
Topics: AIDS Vaccines; Ankyrin Repeat; Antibodies, Neutralizing; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Genetic Therapy; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunotherapy, Adoptive; Peptides; Proteins; Single-Chain Antibodies; Virus Integration; Virus Internalization
PubMed: 28961190
DOI: 10.3390/v9100281 -
Current Opinion in HIV and AIDS May 2017Although approximately 90% of all HIV transmissions in humans occur through mucosal contact, the induction of mucosal anti-HIV immune responses has remained... (Review)
Review
PURPOSE OF REVIEW
Although approximately 90% of all HIV transmissions in humans occur through mucosal contact, the induction of mucosal anti-HIV immune responses has remained understudied. Here we summarize data demonstrating the powerful protection that is achievable at mucosal frontlines through virus-specific mucosal IgA alone or combined with IgG.
RECENT FINDINGS
Passive immunization with different monoclonal antibody subclasses but identical epitope specificity (the conserved V3-loop crown of HIV gp120) has revealed that the dimeric IgA1 (dIgA1) form with its open hinge can prevent simian-human immunodeficiency virus (SHIV) acquisition in rhesus macaques at a higher rate than dIgA2. Both dIgAs neutralized the challenge SHIV equally well. Protection was linked to better virion capture and inhibition of cell-free virus transcytosis by dIgA1. Synergistic interactions at the mucosal level between the IgG1 and dIgA2 versions of this monoclonal antibody yielded complete protection. Active vaccine strategies designed to induce mucosal IgA and systemic/mucosal IgG have given promising data.
SUMMARY
This review seeks to highlight the importance of mucosal IgAs in preventing virus acquisition. Passive immunization gave proof-of-concept for immune exclusion by mucosally administered monoclonal dIgAs. Unanswered questions remain regarding the interplay between mucosal IgA and other host immune defenses, including their induction with active immunization.
Topics: Animals; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunity, Mucosal
PubMed: 28422786
DOI: 10.1097/COH.0000000000000369 -
Vaccine Mar 2015Antibody-inducing vaccines are a major focus in the preventive HIV vaccine field. Because the most common tests for HIV infection rely on detecting antibodies to HIV,... (Review)
Review
Antibody-inducing vaccines are a major focus in the preventive HIV vaccine field. Because the most common tests for HIV infection rely on detecting antibodies to HIV, they may also detect antibodies induced by a candidate HIV vaccine. The detection of vaccine-induced antibodies to HIV by serological tests is most commonly referred to as vaccine-induced sero-reactivity (VISR). VISR can be misinterpreted as a sign of HIV infection in a healthy study participant. In a participant who has developed vaccine-induced antibodies, accurate diagnosis of HIV infection (or lack thereof) may require specialized tests and algorithms (differential testing) that are usually not available in community settings. Organizations sponsoring clinical testing of preventive HIV vaccine candidates have an ethical obligation not only to inform healthy volunteers about the potential problems associated with participating in a clinical trial but also to help manage any resulting issues. This article explores the scope of VISR-related issues that become increasingly prevalent as the search for an effective HIV vaccine continues and will be paramount once a preventive vaccine is deployed. We also describe ways in which organizations conducting HIV vaccine trials have addressed these issues and outline areas where more work is needed.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; HIV Antibodies; HIV Seropositivity; HIV-1; Humans; Informed Consent; Seroconversion
PubMed: 25649349
DOI: 10.1016/j.vaccine.2014.10.040 -
Current Opinion in HIV and AIDS Nov 2016A vaccine that elicits antibody responses that can neutralize the diversity of HIV clades has not yet been achieved, and is a major focus of HIV vaccine research. Here,... (Review)
Review
PURPOSE OF REVIEW
A vaccine that elicits antibody responses that can neutralize the diversity of HIV clades has not yet been achieved, and is a major focus of HIV vaccine research. Here, we provide an update on the barriers to eliciting such antibodies, and how advances in immunogen design may circumvent these roadblocks, focusing on data published in the last year.
RECENT FINDINGS
Studies of how broadly neutralizing antibodies (bNAbs) develop in HIV-infected donors continue to produce key insights, suggesting that for some viral targets there are common pathways to developing breadth. Germline-targeting strategies, that aim to recruit rare precursors of bNAbs, have shown promise in immunogenicity studies, and structural biology has led to advances in immunogen design. Mapping of strain-specific tier 2 vaccine responses has highlighted the challenges that remain in driving antibodies toward breadth.
SUMMARY
Elucidation of the HIV envelope structure, together with an understanding of how bNAbs emerge in vivo has guided the design of new immunogens and vaccine strategies that show promise for eliciting protective antibodies.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Antigens, Viral; HIV; HIV Antibodies; Humans
PubMed: 27559709
DOI: 10.1097/COH.0000000000000317