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The Journal of Infectious Diseases Feb 2021Human immunodeficiency virus (HIV) infection leads to the establishment of a long-lived latent cellular reservoir. One strategy to eliminate quiescent reservoir cells is... (Review)
Review
Human immunodeficiency virus (HIV) infection leads to the establishment of a long-lived latent cellular reservoir. One strategy to eliminate quiescent reservoir cells is to reactivate virus replication to induce HIV envelope glycoprotein (Env) expression on the cell surface exposing them to subsequent antibody targeting. Via the interactions between the antibody Fc domain and Fc-γ receptors (FcγRs) that are expressed on innate effector cells, such as natural killer cells, monocytes, and neutrophils, antibodies can mediate the elimination of infected cells. Over the last decade, a multitude of human monoclonal antibodies that are broadly neutralizing across many HIV-1 subtypes have been identified and are currently being explored for HIV eradication strategies. Antibody development also includes novel Fc engineering approaches to increase engagement of effector cells and optimize antireservoir efficacy. In this review, we discuss the usefulness of antibodies for HIV eradication approaches specifically focusing on antibody-mediated strategies to target latently infected cells and options to increase antibody efficacy.
Topics: Animals; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HIV Antibodies; HIV Infections; HIV-1; Humans; Virus Latency
PubMed: 33586772
DOI: 10.1093/infdis/jiaa165 -
Human Vaccines & Immunotherapeutics May 2017An HIV-1 vaccine is needed to curtail the HIV epidemic. Only one (RV144) out of the 6 HIV-1 vaccine efficacy trials performed showed efficacy. A potential mechanism of... (Review)
Review
An HIV-1 vaccine is needed to curtail the HIV epidemic. Only one (RV144) out of the 6 HIV-1 vaccine efficacy trials performed showed efficacy. A potential mechanism of protection is the induction of functional antibodies to V1V2 region of HIV envelope. The 2 main current approaches to the generation of protective immunity are through broadly neutralizing antibodies (bnAb) and induction of functional antibodies (non-neutralizing Abs with other potential anti-viral functions). Passive immunization using bnAb has advanced into phase II clinical trials. The induction of bnAb using mimics of the natural Env trimer or B-cell lineage vaccine design is still in pre-clinical phase. An attempt at optimization of protective functional antibodies will be assessed next with the efficacy trial (HVTN702) about to start. With on-going optimization of prime/boost strategies, the development of mosaic immunogens, replication competent vectors, and emergence of new strategies designed to induce bnAb, the prospects for a preventive HIV vaccine have never been more promising.
Topics: AIDS Vaccines; Antibodies, Neutralizing; B-Lymphocytes; Clinical Trials as Topic; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunization, Passive
PubMed: 28281871
DOI: 10.1080/21645515.2016.1276138 -
Nature Communications Jun 2023Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV...
Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 and CD8 T cells. Co-culturing CD4 with autologous CD8 T cells from ART-suppressed HIV donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 T cells. This trispecific antibody mediates CD4 and CD8 T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection.
Topics: Animals; HIV Infections; CD8-Positive T-Lymphocytes; HIV-1; CD4-Positive T-Lymphocytes; Virus Latency; HIV Antibodies
PubMed: 37349337
DOI: 10.1038/s41467-023-39265-z -
Current Opinion in HIV and AIDS May 2015To provide an update on neutralizing antibody targets in the context of the recent HIV-1 envelope trimer structure, describe new antibody isolation technologies, and... (Review)
Review
PURPOSE OF REVIEW
To provide an update on neutralizing antibody targets in the context of the recent HIV-1 envelope trimer structure, describe new antibody isolation technologies, and discuss the implications of these data for HIV-1 prevention and therapy.
RECENT FINDINGS
Recent advances in B-cell technologies have dramatically expanded the number of antibodies isolated from HIV-infected donors with broadly neutralizing plasma activity. These, together with the first high-resolution crystal and cryo-electron microscopy (cryo-EM) structures of a cleaved, prefusion HIV-1 trimer, have defined new regions susceptible to neutralization. This year, three epitopes in the gp120-gp41 interface were structurally characterized, highlighting the importance of prefusion gp41 as a target. Similar to many other broadly neutralizing antibody epitopes, these new antibodies define a target that is also highly glycan dependent. Collectively, the epitopes for broadly neutralizing antibodies now reveal a continuum of vulnerability spanning the length of the HIV-1 envelope trimer.
SUMMARY
Progress in the last year has provided support for the use of rationally stabilized whole HIV-1 trimers as immunogens for eliciting antibodies to multiple epitopes. Furthermore, the increasing number of broad and potent antibodies with the potential for synergistic/complementary combinations opens up new avenues for preventing and treating HIV-1 infection.
Topics: Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 25760932
DOI: 10.1097/COH.0000000000000153 -
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 -
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 -
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 -
Microbiology Spectrum Aug 2014This article focuses on a novel vaccine strategy known as vector-mediated antibody gene transfer, with a particular focus on human immunodeficiency virus (HIV). This... (Review)
Review
This article focuses on a novel vaccine strategy known as vector-mediated antibody gene transfer, with a particular focus on human immunodeficiency virus (HIV). This strategy provides a solution to the problem of current vaccines that fail to generate neutralizing antibodies to prevent HIV-1 infection and AIDS. Antibody gene transfer allows for predetermination of antibody affinity and specificity prior to "immunization" and avoids the need for an active humoral immune response against the HIV envelope protein. This approach uses recombinant adeno-associated viral (rAAV) vectors, which have been shown to transduce muscle with high efficiency and direct the long-term expression of a variety of transgenes, to deliver the gene encoding a broadly neutralizing antibody into the muscle. Following rAAV vector gene delivery, the broadly neutralizing antibodies are endogenously synthesized in myofibers and passively distributed to the circulatory system. This is an improvement over classical passive immunization strategies that administer antibody proteins to the host to provide protection from infection. Vector-mediated gene transfer studies in mice and monkeys with anti-HIV and simian immunodeficiency virus (SIV)-neutralizing antibodies demonstrated long-lasting neutralizing activity in serum with complete protection against intravenous challenge with virulent HIV and SIV. These results indicate that existing potent anti-HIV antibodies can be rapidly moved into the clinic. However, this methodology need not be confined to HIV. The general strategy of vector-mediated antibody gene transfer can be applied to other difficult vaccine targets such as hepatitis C virus, malaria, respiratory syncytial virus, and tuberculosis.
Topics: Adenoviridae; Animals; Antibodies, Neutralizing; Gene Expression; Genetic Vectors; HIV; HIV Antibodies; Haplorhini; Humans; Immunization, Passive; Mice; Recombinant Proteins; Simian Immunodeficiency Virus; Transduction, Genetic
PubMed: 26104192
DOI: 10.1128/microbiolspec.AID-0016-2014 -
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 -
Frontiers in Immunology 2023Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low... (Review)
Review
Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low interest and thus focus the immune system on highly therapeutic epitopes. This shielding strategy is inspired by viruses such as influenza and HIV, which are able to escape the immune system by incorporating additional glycosylation and preventing the binding of therapeutic antibodies. Interestingly, the glycan masking technique is mainly used in vaccine design to fight the same viruses that naturally use glycans to evade the immune system. In this review we report the major successes obtained with the glycan masking technique in epitope-focused vaccine design. We focus on the choice of the target antigen, the strategy for immunogen design and the relevance of the carrier vector to induce a strong immune response. Moreover, we will elucidate the different applications that can be accomplished with glycan masking, such as shifting the immune response from hyper-variable epitopes to more conserved ones, focusing the response on known therapeutic epitopes, broadening the response to different viral strains/sub-types and altering the antigen immunogenicity to elicit higher or lower immune response, as desired.
Topics: HIV Antibodies; Antibodies, Neutralizing; Epitopes; Polysaccharides; HIV-1
PubMed: 37033915
DOI: 10.3389/fimmu.2023.1126034