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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 -
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 -
AIDS Research and Human Retroviruses Aug 2017It has been known for more than 30 years that HIV-1 infection drives a very potent B cell response resulting in the production of anti-HIV-1 antibodies targeting several... (Review)
Review
It has been known for more than 30 years that HIV-1 infection drives a very potent B cell response resulting in the production of anti-HIV-1 antibodies targeting several viral proteins, particularly its envelope glycoproteins (Env). Env epitopes are exposed on the surfaces of viral particles and infected cells where they are targets of potentially protective antibodies. These antibodies can interdict infection by neutralization and there is strong evidence suggesting that Fc-mediated effector function can also contribute to protection. Current evidence suggests that Fc-mediated effector function plays a role in protection against infection by broadly neutralizing antibodies and it might be important for protection by non-neutralizing antibodies. Fc-mediated effector function includes diverse mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), antibody-mediated complement activation, antibody-dependent cellular phagocytosis, antibody-dependent cell-mediated virus inhibition, antibody-mediated trancytosis inhibition, and antibody-mediated virus opsonization. All these functions could be beneficial in fighting viral infections, including HIV-1. In this perspective, we discuss the latest developments in ADCC research discussed at the HIVR4P satellite session on non-neutralizing antibodies, with emphasis on the mechanisms of ADCC resistance used by HIV-1, the structural basis of epitopes recognized by antibodies that mediate ADCC, natural killer-cell education and ADCC, and murine models to study ADCC against HIV-1.
Topics: Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; Complement Activation; HIV Antibodies; HIV Infections; HIV-1; Humans; Phagocytosis
PubMed: 28084796
DOI: 10.1089/AID.2016.0299 -
PLoS Pathogens Oct 2023Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally... (Review)
Review
Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally elicited following viral infection and have been characterized in viral infections such as influenza, rotavirus, cytomegalovirus, HIV, and SARS-CoV-2. It has been widely assumed that these nonneutralizing antibodies do not function in a protective way in vivo and therefore are not desirable targets of antiviral interventions; however, increasing evidence now shows this not to be true. Several virus-specific nonneutralizing antibody responses have been correlated with protection in human studies and also shown to significantly reduce virus replication in animal models. The mechanisms by which many of these antibodies function is only now coming to light. While nonneutralizing antibodies cannot prevent viruses entering their host cell, nonneutralizing antibodies work in the extracellular space to recruit effector proteins or cells that can destroy the antibody-virus complex. Other nonneutralizing antibodies exert their effects inside cells, either by blocking the virus life cycle directly or by recruiting the intracellular Fc receptor TRIM21. In this review, we will discuss the multitude of ways in which nonneutralizing antibodies function against a range of viral infections.
Topics: Animals; Humans; Antibodies, Viral; Virus Diseases; Influenza, Human; Receptors, Fc; Antiviral Agents; Antibodies, Neutralizing; HIV Antibodies
PubMed: 37796829
DOI: 10.1371/journal.ppat.1011670 -
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 -
Frontiers in Immunology 2018
Topics: Antibodies, Neutralizing; B-Lymphocytes; HIV Antibodies; HIV Infections; Humans
PubMed: 29515590
DOI: 10.3389/fimmu.2018.00297 -
Viruses Apr 2018An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV-1 epidemic. However, despite significant efforts to develop a safe and effective... (Review)
Review
An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV-1 epidemic. However, despite significant efforts to develop a safe and effective vaccine, the modestly protective RV144 trial remains the only efficacy trial to provide some level of protection against HIV-1 acquisition. This review will outline the history of HIV vaccine development, novel technologies being applied to HIV vaccinology and immunogen design, as well as the studies that are ongoing to advance our understanding of vaccine-induced immune correlates of protection.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Clinical Trials as Topic; Drug Evaluation, Preclinical; HIV Antibodies; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Immunogenicity, Vaccine; Outcome Assessment, Health Care; Structure-Activity Relationship; Vaccination; Viral Proteins
PubMed: 29614779
DOI: 10.3390/v10040167 -
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