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Cell Dec 2019B cell receptor (BCR) sequencing is a powerful tool for interrogating immune responses to infection and vaccination, but it provides limited information about the...
B cell receptor (BCR) sequencing is a powerful tool for interrogating immune responses to infection and vaccination, but it provides limited information about the antigen specificity of the sequenced BCRs. Here, we present LIBRA-seq (linking B cell receptor to antigen specificity through sequencing), a technology for high-throughput mapping of paired heavy- and light-chain BCR sequences to their cognate antigen specificities. B cells are mixed with a panel of DNA-barcoded antigens so that both the antigen barcode(s) and BCR sequence are recovered via single-cell next-generation sequencing. Using LIBRA-seq, we mapped the antigen specificity of thousands of B cells from two HIV-infected subjects. The predicted specificities were confirmed for a number of HIV- and influenza-specific antibodies, including known and novel broadly neutralizing antibodies. LIBRA-seq will be an integral tool for antibody discovery and vaccine development efforts against a wide range of antigen targets.
Topics: Antibodies, Neutralizing; Antigens; Cells, Cultured; Epitope Mapping; Epitopes; HEK293 Cells; HIV Antibodies; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Receptors, Antigen, B-Cell; Sequence Analysis, DNA; Single-Cell Analysis; THP-1 Cells
PubMed: 31787378
DOI: 10.1016/j.cell.2019.11.003 -
Seminars in Immunology Jan 2021HIV is a virus that remains a major health concern and results in an infection that has no cure even after over 30 years since its discovery. As such, HIV vaccine... (Review)
Review
HIV is a virus that remains a major health concern and results in an infection that has no cure even after over 30 years since its discovery. As such, HIV vaccine discovery continues to be an area of intensive research. In this review, we summarize the most recent HIV vaccine efficacy trials, clinical trials initiated within the last 3 years, and discuss prominent improvements that have been made in prophylactic HIV vaccine designs.
Topics: Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Vaccinology
PubMed: 34272086
DOI: 10.1016/j.smim.2021.101470 -
Current Opinion in HIV and AIDS May 2014
Topics: AIDS Vaccines; HIV Antibodies; HIV Infections; Humans
PubMed: 24670323
DOI: 10.1097/COH.0000000000000060 -
Nature Reviews. Drug Discovery Dec 2016HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to... (Review)
Review
HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4 T cells and thus limit the spread of progeny virus. Recent innovations in antibody engineering have resulted in novel immunotherapeutics such as bispecific dual-affinity re-targeting (DART) molecules and other bi- and trispecific antibody designs that can recognize HIV-1 Env and recruit cytotoxic effector cells to kill CD4 T cells latently infected with HIV-1. Here, we review these immunotherapies, which are designed with the goal of curing HIV-1 infection.
Topics: AIDS Vaccines; Animals; Antibodies, Monoclonal; Antibody Specificity; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunotherapy; env Gene Products, Human Immunodeficiency Virus
PubMed: 27725635
DOI: 10.1038/nrd.2016.173 -
Immunological Reviews Jan 2017The antiviral activity of antibodies reflects the bifunctional properties of these molecules. While the Fab domains mediate highly specific antigenic recognition to... (Review)
Review
The antiviral activity of antibodies reflects the bifunctional properties of these molecules. While the Fab domains mediate highly specific antigenic recognition to block virus entry, the Fc domain interacts with diverse types of Fcγ receptors (FcγRs) expressed on the surface of effector leukocytes to induce the activation of distinct immunomodulatory pathways. Fc-FcγR interactions are tightly regulated to control IgG-mediated inflammation and immunity and are largely determined by the structural heterogeneity of the IgG Fc domain, stemming from differences in the primary amino acid sequence of the various subclasses, as well as the structure and composition of the Fc-associated N-linked glycan. Engagement of specific FcγR types on effector leukocytes has diverse consequences that affect several aspects of innate and adaptive immunity. In this review, we provide an overview of the complexity of FcγR-mediated pathways, discussing their role in the in vivo protective activity of anti-HIV-1 antibodies. We focus on recent studies on broadly neutralizing anti-HIV-1 antibodies that revealed that Fc-FcγR interactions are required to achieve full therapeutic activity through clearance of IgG-opsonized virions and elimination of HIV-infected cells. Manipulation of Fc-FcγR interactions to specifically activate distinct FcγR-mediated pathways has the potential to affect downstream effector responses, influencing thereby the in vivo protective activity of anti-HIV-1 antibodies; a strategy that has already been successfully applied to other IgG-based therapeutics, substantially improving their clinical efficacy.
Topics: Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunoglobulin Fab Fragments; Immunomodulation; Immunotherapy; Phagocytosis; Receptors, IgG; Viral Load
PubMed: 28133801
DOI: 10.1111/imr.12482 -
Antiviral Research Feb 2024Despite the ability to suppress viral replication using anti-retroviral therapy (ART), HIV-1 remains a global public health problem. Curative strategies for HIV-1 have... (Review)
Review
Despite the ability to suppress viral replication using anti-retroviral therapy (ART), HIV-1 remains a global public health problem. Curative strategies for HIV-1 have to target and eradicate latently infected cells across the body, i.e. the viral reservoir. Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have the capacity to neutralize virions and bind to infected cells to initiate elimination of these cells. To improve the efficacy of bNAbs in terms of viral suppression and viral reservoir eradication, next generation antibodies (Abs) are being developed that address the current limitations of Ab treatment efficacy; (1) low antigen (Env) density on (reactivated) HIV-1 infected cells, (2) high viral genetic diversity, (3) exhaustion of immune cells and (4) short half-life of Abs. In this review we summarize and discuss preclinical and clinical studies in which anti-HIV-1 Abs demonstrated potent viral control, and describe the development of engineered Abs that could address the limitations described above. Next generation Abs with optimized effector function, avidity, effector cell recruitment and immune cell activation have the potential to contribute to an HIV-1 cure or durable control.
Topics: Humans; Broadly Neutralizing Antibodies; Antibodies, Neutralizing; HIV-1; HIV Antibodies; HIV Infections
PubMed: 38158130
DOI: 10.1016/j.antiviral.2023.105788 -
Science (New York, N.Y.) Sep 2013Despite 30 years of study, there is no HIV-1 vaccine and, until recently, there was little hope for a protective immunization. Renewed optimism in this area of research... (Review)
Review
Despite 30 years of study, there is no HIV-1 vaccine and, until recently, there was little hope for a protective immunization. Renewed optimism in this area of research comes in part from the results of a recent vaccine trial and the use of single-cell antibody-cloning techniques that uncovered naturally arising, broad and potent HIV-1-neutralizing antibodies (bNAbs). These antibodies can protect against infection and suppress established HIV-1 infection in animal models. The finding that these antibodies develop in a fraction of infected individuals supports the idea that new approaches to vaccination might be developed by adapting the natural immune strategies or by structure-based immunogen design. Moreover, the success of passive immunotherapy in small-animal models suggests that bNAbs may become a valuable addition to the armamentarium of drugs that work against HIV-1.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunotherapy; Viral Envelope Proteins
PubMed: 24031012
DOI: 10.1126/science.1241144 -
Cell Chemical Biology May 2022Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the... (Review)
Review
Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the quality of life, reduced mortality, and decreased the incidence of AIDS and HIV-related conditions. Currently, however, affected individuals are typically on a lifetime course of several therapeutic drugs, all with the potential for associated toxicity and emergence of resistance. This calls for development of novel, potent, and broad anti-HIV agents able to stop the spread of HIV/AIDS. Significant progress has been made toward identification of anti-HIV-1 broadly neutralizing antibodies (bNAbs). However, antibody-based drugs are costly to produce and store. Administration (by injection only) and other obstacles limit clinical use. In recent years, several highly promising small-molecule HIV-1 entry inhibitors targeting the epitopes of bNAbs have been developed. These newly developed compounds are the focus of the present article.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; Quality of Life; env Gene Products, Human Immunodeficiency Virus
PubMed: 35353988
DOI: 10.1016/j.chembiol.2022.03.009 -
The Journal of Experimental Medicine Jan 2017AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly... (Review)
Review
AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly desirable. Most vaccines in clinical use today prevent infection because they elicit antibodies that block pathogen entry. Consistent with this general rule, studies in experimental animals have shown that broadly neutralizing antibodies to HIV-1 can prevent infection, suggesting that a vaccine that elicits such antibodies would be protective. However, despite significant efforts over the last 30 years, attempts to elicit broadly HIV-1 neutralizing antibodies by vaccination failed until recent experiments in genetically engineered mice were finally successful. Here, we review the key breakthroughs and remaining obstacles to the development of active and passive HIV-1 vaccines.
Topics: AIDS Vaccines; Antibodies, Monoclonal; Antibodies, Neutralizing; Genetic Engineering; HIV Antibodies; HIV-1; Humans; Immunization, Passive; Mutation; Vaccination
PubMed: 28003309
DOI: 10.1084/jem.20161765 -
Trends in Molecular Medicine Mar 2019After years of continuous exposure to HIV envelope antigens, a minority of HIV-infected individuals develop a cognate polyclonal humoral response comprising very potent... (Review)
Review
After years of continuous exposure to HIV envelope antigens, a minority of HIV-infected individuals develop a cognate polyclonal humoral response comprising very potent and extremely cross-reactive neutralizing antibodies [broadly neutralizing antibodies (bNAbs)]. Isolated bNAbs derived from memory B cell pools have been the focus of intense studies over the past decade. However, it is not yet known how to translate the features of bNAbs into practical HIV prevention methods. In this review, we attempt to seek insights from emerging information about the human broadly neutralizing plasma response as well as its frequency, clonal composition, specificity, potency, and commonality among infected subjects. We also consider how this information points to selecting and prioritizing certain epitope targets and strategies for HIV vaccine design.
Topics: Animals; B-Lymphocytes; Broadly Neutralizing Antibodies; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; T-Lymphocyte Subsets; Viral Proteins
PubMed: 30792120
DOI: 10.1016/j.molmed.2019.01.007