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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 -
Nature Jun 2022Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV). However, eradication of the virus in individuals with HIV has not been... (Randomized Controlled Trial)
Randomized Controlled Trial
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV). However, eradication of the virus in individuals with HIV has not been possible to date. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; Double-Blind Method; HIV Antibodies; HIV Infections; HIV-1; Humans; Viral Load; Viremia
PubMed: 35650437
DOI: 10.1038/s41586-022-04797-9 -
Expert Opinion on Biological Therapy Aug 2020G protein-coupled receptors (GPCRs) play key roles in many biological functions and are linked to many diseases across all therapeutic areas. As such, GPCRs represent a... (Review)
Review
INTRODUCTION
G protein-coupled receptors (GPCRs) play key roles in many biological functions and are linked to many diseases across all therapeutic areas. As such, GPCRs represent a significant opportunity for antibody-based therapeutics.
AREAS COVERED
The structure of the major GPCR families is summarized in the context of choice of antigen source employed in the drug discovery process and receptor biology considerations which may impact on targeting strategies. An overview of the therapeutic GPCR-antibody target landscape and the diversity of current therapeutic programs is provided along with summary case studies for marketed antibody drugs or those in advanced clinical studies. Antibodies in early clinical studies and the emergence of next-generation modalities are also highlighted.
EXPERT OPINION
The GPCR-antibody pipeline has progressed significantly with a number of technical developments enabling the successful resolution of some of the challenges previously encountered and this has contributed to the growing interest in antibody-based therapeutics addressing this target class.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Gastrointestinal Neoplasms; HIV Antibodies; Humans; Receptors, G-Protein-Coupled
PubMed: 32264722
DOI: 10.1080/14712598.2020.1745770 -
Nature Biotechnology Aug 2022Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of...
Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of this approach would require specialized medical centers, technically demanding protocols and major histocompatibility complex compatibility of donor cells and recipients. Here we report in vivo B cell engineering using two adeno-associated viral vectors, with one coding for Staphylococcus aureus Cas9 (saCas9) and the other for 3BNC117, an anti-HIV bNAb. After intravenously injecting the vectors into mice, we observe successful editing of B cells leading to memory retention and bNAb secretion at neutralizing titers of up to 6.8 µg ml. We observed minimal clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 off-target cleavage as detected by unbiased CHANGE-sequencing analysis, whereas on-target cleavage in undesired tissues is reduced by expressing saCas9 from a B cell-specific promoter. In vivo B cell engineering to express therapeutic antibodies is a safe, potent and scalable method, which may be applicable not only to infectious diseases but also in the treatment of noncommunicable conditions, such as cancer and autoimmune disease.
Topics: Animals; Antibodies, Neutralizing; B-Lymphocytes; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Mice; Staphylococcus aureus
PubMed: 35681059
DOI: 10.1038/s41587-022-01328-9 -
International Journal of STD & AIDS Mar 2015Failure to understand the risk of false-negative HIV test results during the window period results in anxiety. Patients typically want accurate test results as soon as... (Review)
Review
Failure to understand the risk of false-negative HIV test results during the window period results in anxiety. Patients typically want accurate test results as soon as possible while clinicians prefer to wait until the probability of a false-negative is virtually nil. This review summarizes the median window periods for third-generation antibody and fourth-generation HIV tests and provides the probability of a false-negative result for various days post-exposure. Data were extracted from published seroconversion panels. A 10-day eclipse period was used to estimate days from infection to first detection of HIV RNA. Median (interquartile range) days to seroconversion were calculated and probabilities of a false-negative result at various time periods post-exposure are reported. The median (interquartile range) window period for third-generation tests was 22 days (19-25) and 18 days (16-24) for fourth-generation tests. The probability of a false-negative result is 0.01 at 80 days' post-exposure for third-generation tests and at 42 days for fourth-generation tests. The table of probabilities of falsely-negative HIV test results may be useful during pre- and post-test HIV counselling to inform co-decision making regarding the ideal time to test for HIV.
Topics: AIDS Serodiagnosis; Counseling; False Negative Reactions; Female; HIV Antibodies; HIV Seropositivity; Humans; Male; Polymerase Chain Reaction; Predictive Value of Tests; RNA, Viral; Reagent Kits, Diagnostic; Sensitivity and Specificity; Time Factors
PubMed: 25033879
DOI: 10.1177/0956462414542987 -
Clinical Immunology (Orlando, Fla.) Dec 2023Anti-HIV broadly neutralizing antibodies (bNAbs) offer a novel approach to treating, preventing, or curing HIV. Pre-clinical models and clinical trials involving the... (Review)
Review
Anti-HIV broadly neutralizing antibodies (bNAbs) offer a novel approach to treating, preventing, or curing HIV. Pre-clinical models and clinical trials involving the passive transfer of bNAbs have demonstrated that they can control viremia and potentially serve as alternatives or complement antiretroviral therapy (ART). However, antibody decay, persistent latent reservoirs, and resistance impede bNAb treatment. This review discusses recent advancements and obstacles in applying bNAbs and proposes strategies to enhance their therapeutic potential. These strategies include multi-epitope targeting, antibody half-life extension, combining with current and newer antiretrovirals, and sustained antibody secretion.
Topics: Humans; Broadly Neutralizing Antibodies; Antibodies, Neutralizing; HIV-1; HIV Infections; HIV Antibodies
PubMed: 37852345
DOI: 10.1016/j.clim.2023.109809 -
Frontiers in Immunology 2018
Topics: Antibodies, Neutralizing; B-Lymphocytes; HIV Antibodies; HIV Infections; Humans
PubMed: 29515590
DOI: 10.3389/fimmu.2018.00297 -
Seminars in Immunology Jan 2021Despite immense progress in our ability to prevent and treat HIV-1 infection, HIV-1 remains an incurable disease and a highly efficacious HIV-1 vaccine is not yet... (Review)
Review
Despite immense progress in our ability to prevent and treat HIV-1 infection, HIV-1 remains an incurable disease and a highly efficacious HIV-1 vaccine is not yet available. Additional tools to prevent and treat HIV-1 are therefore necessary. The identification of potent and broadly neutralizing antibodies (bNAbs) against HIV-1 has revolutionized the field and may prove clinically useful. Significant advances have been made in identifying broader and more potent antibodies, characterizing antibodies in preclinical animal models, engineering antibodies to extend half-life and expand breadth and functionality, and evaluating the efficacy of single bNAbs and bNAb combinations in people with and without HIV-1. Here, we review recent progress in developing bNAbs for the prevention and treatment of HIV-1.
Topics: Animals; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 33858765
DOI: 10.1016/j.smim.2021.101475 -
The Journal of Biological Chemistry Apr 2017The viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and... (Review)
Review
The viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion machinery. This work advances our understanding of host-virus interactions and provides a compelling case for considering the host immune system in studies of restriction factor mechanisms.
Topics: Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Membrane Proteins; Protein Folding; Virus Internalization
PubMed: 28389578
DOI: 10.1074/jbc.H117.777714