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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 -
Frontiers in Immunology 2021The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this...
The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality.
Topics: Antibody-Dependent Cell Cytotoxicity; Antibody-Dependent Enhancement; Broadly Neutralizing Antibodies; Genetic Engineering; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Neutralization Tests; Phagocytosis; Protein Binding; Receptors, IgG; THP-1 Cells
PubMed: 34566999
DOI: 10.3389/fimmu.2021.733958 -
Frontiers in Public Health 2021Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be... (Review)
Review
Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be necessary to end the epidemic and remain a top public health priority. Antiretroviral therapy (ART) has been effective in extending lives, but at a cost of lifelong adherence to treatment. Broadly neutralizing antibodies (bNAbs) are directed to conserved regions of the HIV-1 envelope glycoprotein trimer (Env) and can block infection if present at the time of viral exposure. The therapeutic application of bNAbs holds great promise, and progress is being made toward their development for widespread clinical use. Compared to the current standard of care of small molecule-based ART, bNAbs offer: (1) reduced toxicity; (2) the advantages of extended half-lives that would bypass daily dosing requirements; and (3) the potential to incorporate a wider immune response through Fc signaling. Recent advances in discovery technology can enable system-wide mining of the immunoglobulin repertoire and will continue to accelerate isolation of next generation potent bNAbs. Passive transfer studies in pre-clinical models and clinical trials have demonstrated the utility of bNAbs in blocking or limiting transmission and achieving viral suppression. These studies have helped to define the window of opportunity for optimal intervention to achieve viral clearance, either using bNAbs alone or in combination with ART. None of these advances with bNAbs would be possible without technological advancements and expanding the cohorts of donor participation. Together these elements fueled the remarkable growth in bNAb development. Here, we review the development of bNAbs as therapies for HIV-1, exploring advances in discovery, insights from animal models and early clinical trials, and innovations to optimize their clinical potential through efforts to extend half-life, maximize the contribution of Fc effector functions, preclude escape through multiepitope targeting, and the potential for sustained delivery.
Topics: Animals; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; Epitopes; HIV Antibodies; HIV Infections; HIV-1; env Gene Products, Human Immunodeficiency Virus
PubMed: 34123998
DOI: 10.3389/fpubh.2021.690017 -
Trends in Molecular Medicine Nov 2022Broadly neutralizing antibodies (bNAbs), when administered through passive immunization, are protective against HIV-1 infection. Current HIV-1 vaccine strategies are... (Review)
Review
Broadly neutralizing antibodies (bNAbs), when administered through passive immunization, are protective against HIV-1 infection. Current HIV-1 vaccine strategies are aimed at guiding the immune system to make bNAbs by mimicking their development during infection. Somatic hypermutation of the variable region is known to be crucial for the development of bNAbs. More recently, however, studies have shown how class-switch recombination (CSR) resulting in the generation of different antibody isotypes may serve as an additional mechanism through which antibodies can gain neutralization breadth and potency. In this review, we discuss the importance of different antibody isotypes for HIV-1 neutralization breadth and potency and how this information can be leveraged to improve passive and active immunization against HIV-1.
Topics: Humans; HIV-1; HIV Antibodies; Broadly Neutralizing Antibodies; Antibodies, Neutralizing; Immunoglobulin Isotypes; HIV Infections
PubMed: 36117072
DOI: 10.1016/j.molmed.2022.08.010 -
Trends in Microbiology Sep 2022Glycans are repeating carbohydrate structures added as post-translational modifications (PTMs) to proteins, forming glycoproteins. Self-glycans found on human cells, and... (Review)
Review
Glycans are repeating carbohydrate structures added as post-translational modifications (PTMs) to proteins, forming glycoproteins. Self-glycans found on human cells, and viral glycoproteins produced in host cells, are generally weakly immunogenic, which is necessary to avoid autoimmunity. This feature is exploited by many pathogenic viruses, which glycosylate surface proteins to evade or reduce immune recognition. The HIV type-1 (HIV-1) envelope glycoprotein (Env) is heavily glycosylated, which broadly acts to shield neutralisation-relevant protein surfaces with immunorecessive self-glycans to hinder B cell recognition. However, a small subset of HIV-1-infected individuals develops potent broadly neutralising antibodies (bnAbs), many of which directly engage the glycan shield. This provides hope that such antibodies could be elicited via vaccination and help to provide protective immunity. However, HIV-1 vaccine candidates have thus far failed to fully recapitulate such glycan-specific neutralising responses. In this review we consider the fundamental glycoimmunology and structural biology that underpin glycans in antibody evasion and as antibody targets and discuss potential approaches to harness glycan targeting for HIV-1 vaccine design.
Topics: Antibodies, Neutralizing; Glycoproteins; HIV Antibodies; HIV Infections; HIV-1; Humans; Polysaccharides; env Gene Products, Human Immunodeficiency Virus
PubMed: 35279348
DOI: 10.1016/j.tim.2022.02.004 -
Frontiers in Immunology 2022Infants acquire maternal antibodies by Fc receptor transcytosis across the placenta during pregnancy. Fc receptors are expressed on immune cells and are important for...
INTRODUCTION
Infants acquire maternal antibodies by Fc receptor transcytosis across the placenta during pregnancy. Fc receptors are expressed on immune cells and are important for activation of effector cell functions.
METHODS
In this study, we evaluated Fc receptor engagement and ADCC activity of plasma binding antibodies from human immunodeficiency virus-1 (HIV) -infected mothers and to identify factors that may contribute to protection from HIV vertical transmission.
RESULTS
HIV-specific binding and Fc receptor engagement of plasma antibodies varied between mothers by transmission status and infants by infection status. Non-transmitting (NT) mothers and HIV-uninfected infants had antibodies with higher neonatal Fc receptor (FcRn) and FcγR engagement, as compared to transmitting (T) mothers and HIV+ infants, respectively. A significant inverse correlation between plasma antibody FcRn and FcγR engagement was observed for T mothers, but not NT mothers. Conversely, a significant direct correlation was observed between plasma antibody FcRn and FcγR engagement for HIV- infants, but not for HIV+ infants. Consequently, we observed significantly higher plasma antibody ADCC potency and breadth in HIV- infants, as compared to HIV+ infants. However, no differences in overall ADCC potency and breadth were observed between mothers. FcRn-engagement of HIV-specific antibodies in both mothers and infants predicted a lack of vertical transmission of HIV.
DISCUSSION
This study indicates that HIV-uninfected infants acquire HIV-specific antibodies with greater Fc receptor engagement and thus, greater ADCC capacity.
Topics: Infant, Newborn; Pregnancy; Female; Infant; Humans; HIV-1; HIV Infections; Receptors, IgG; HIV Antibodies; Receptors, Fc
PubMed: 36578481
DOI: 10.3389/fimmu.2022.1051501 -
The New England Journal of Medicine Sep 2021
Topics: Conjunctival Neoplasms; HIV Antibodies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Sarcoma, Kaposi
PubMed: 34525288
DOI: 10.1056/NEJMicm2105217 -
Chembiochem : a European Journal of... Apr 2022Oligomannose-type glycans on the spike protein of HIV-1 constitute relevant epitopes to elicit broadly neutralizing antibodies (bnAbs). Herein we describe an improved...
Oligomannose-type glycans on the spike protein of HIV-1 constitute relevant epitopes to elicit broadly neutralizing antibodies (bnAbs). Herein we describe an improved synthesis of α- and β-linked hepta- and nonamannosyl ligands that were subsequently converted into BSA and CRM neoglycoconjugates. We assembled the ligands from anomeric 3-azidopropyl spacer glycosides from select 3-O-protected thiocresyl mannoside donors. Chain extensions were achieved using [4+3] or [4+5] block synthesis of thiocresyl and trichloroacetimidate glycosyl donors. Subsequent global deprotection generated the 3-aminopropyl oligosaccharide ligands. ELISA binding data obtained with the β-anomeric hepta- and nonamannosyl conjugates with a selection of HIV-1 bnAbs showed comparable binding of both mannosyl ligands by Fab fragments yet lesser binding of the nonasaccharide conjugate by the corresponding IgG antibodies. These results support previous observations that a complete Man structure might not be the preferred antigenic binding motif for some oligomannose-specific antibodies, and have implications for glycoside designs to elicit oligomannose-targeted HIV-1-neutralizing antibodies.
Topics: Antibodies, Neutralizing; Epitopes; HIV Antibodies; HIV-1; Humans; Ligands; Male
PubMed: 35104013
DOI: 10.1002/cbic.202200061 -
Clinical Infectious Diseases : An... Nov 2022Broadly neutralizing antibodies directed against human immunodeficiency virus (HIV) offer promise as long-acting agents for prevention and treatment of HIV. Progress and...
Broadly neutralizing antibodies directed against human immunodeficiency virus (HIV) offer promise as long-acting agents for prevention and treatment of HIV. Progress and challenges are discussed. Lessons may be learned from the development of monoclonal antibodies to treat and prevent COVID-19.
Topics: Humans; HIV Antibodies; Antibodies, Monoclonal; COVID-19; HIV Infections; Antineoplastic Agents, Immunological; HIV-1
PubMed: 36410387
DOI: 10.1093/cid/ciac751 -
PLoS Pathogens Jun 2023The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing...
The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10-1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998-2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.
Topics: Humans; HIV Infections; HIV Antibodies; Broadly Neutralizing Antibodies; Antibodies, Neutralizing; HIV-1; HIV Seropositivity; Polysaccharides
PubMed: 37384759
DOI: 10.1371/journal.ppat.1011469