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Current Opinion in HIV and AIDS Jul 2019The review recalls recent findings regarding the induction of vaccinal effects by HIV-1 broadly neutralizing antibodies (bNAbs) and highlights potential therapeutic... (Review)
Review
PURPOSE OF REVIEW
The review recalls recent findings regarding the induction of vaccinal effects by HIV-1 broadly neutralizing antibodies (bNAbs) and highlights potential therapeutic strategies to exploit such immunomodulatory properties.
RECENT FINDINGS
Studies in different animal models have shown that mAbs can generate long-lasting protective immunity. Induction of this vaccinal effect by HIV-1 bNAbs has also been more recently reported in animal models of HIV-1 infection. Notably, bNAbs treatment of macaques infected with the chimeric simian-human immunodeficiency virus (SHIV) improved both humoral and cellular adaptive immune responses that contributed to disease control. Importantly, this concept has been extended to HIV-1-infected patients as enhancement of humoral responses was recently reported in HIV-1 patients treated with bNAbs. Studies aiming at elucidating the mechanisms underlying these immunomodulatory properties of bNAbs have identified a role for immune complexes in shaping immune responses against HIV-1. They also highlight different Fc (fragment crystallizable) region effector functions that might be required for the enhancement of HIV-1 immune responses upon bNAbs treatment.
SUMMARY
HIV-1 bNAbs can elicit protective adaptive immune responses through mechanisms involving multiple cellular and molecular actors of the immune system. Harnessing these mechanisms will be crucial to achieve protective immunity against HIV-1 infection by bNAbs.
Topics: Animals; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 30973419
DOI: 10.1097/COH.0000000000000555 -
Nature Immunology Nov 2018In this Review, we highlight some recent developments in the discovery and application of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV);... (Review)
Review
In this Review, we highlight some recent developments in the discovery and application of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV); i.e., antibodies able to neutralize diverse isolates of HIV. We consider the characterization of novel bnAbs, recent data on the effects of bnAbs in vivo in humans and animal models, and the importance of both kinds of data for the application of Abs to prophylaxis and therapy and to guide vaccine design. We seek to place newly discovered bnAbs in the context of existing bnAbs, and we explore the various characteristics of the antibodies that are most desirable for different applications.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; Humans
PubMed: 30333615
DOI: 10.1038/s41590-018-0235-7 -
Clinical and Vaccine Immunology : CVI Feb 2016Extensive studies have demonstrated that infant immune responses are distinct from those of adults. Despite these differences, infant immunization can elicit protective... (Review)
Review
Extensive studies have demonstrated that infant immune responses are distinct from those of adults. Despite these differences, infant immunization can elicit protective immune responses at levels comparable to or, in some cases, higher than adult immune responses to many vaccines. To date, only a few HIV vaccine candidates have been tested in infant populations, and none of them evaluated vaccine efficacy. Recent exciting studies showing that HIV-infected infants can develop broad neutralizing antibody responses and that some HIV vaccine regimens can elicit high levels of potentially protective antibodies in infants provide support for the development and testing of HIV vaccines in pediatric populations. In this review, we discuss the differences in adult and infant immune responses in the setting of HIV infection and vaccination.
Topics: AIDS Vaccines; Adult; Aging; Antibodies, Neutralizing; Child; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunity, Cellular; Immunity, Humoral; Infant; Vaccination; Vaccines, DNA
PubMed: 26656117
DOI: 10.1128/CVI.00565-15 -
Trends in Immunology Mar 2021'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While... (Review)
Review
'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While observations of antibody convergence across individuals support the assumption that responses may be replicated, the diversity of humoral immunity and the process of antibody selection are rooted in stochasticity. Drawing from experience with in vitro antibody engineering by directed evolution, we consider how antibody selection may be driven, as in germline-targeting vaccine approaches to elicit broadly neutralizing antibodies and illustrate the potential consequences of over-defining a template antibody response. We posit that the prospective definition of template antibody responses and the odds of replicating them must be considered within the randomness of humoral immunity.
Topics: Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV-1; Humans; Prospective Studies
PubMed: 33514459
DOI: 10.1016/j.it.2021.01.001 -
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 -
Journal of Chemical Information and... Jan 2022The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of...
The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied. Accelerated molecular dynamics (aMD) and ab initio hybrid molecular dynamics have been combined to determine the most persistent interactions between the most populated conformations of the antibody-antigen complex under physiological conditions. The results show the most persistent receptor-binding mapping in the conformations of the antibody-antigen interface in solution. The binding-free-energy decomposition reveals a small enhancement in the contribution played by the CDR-H3 region to the b12-gp120 interface compared to the crystal structure.
Topics: Amino Acid Sequence; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunoglobulin G
PubMed: 34971312
DOI: 10.1021/acs.jcim.1c01143 -
Frontiers in Cellular and Infection... 2022The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and...
The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and catalyze rational vaccine development. Traditional mAb discovery is a costly and labor-intensive process, although recent advances in single-cell genomics using emulsion microfluidics allow simultaneous processing of thousands of individual cells. Here we present a streamlined method for isolation and analysis of large numbers of antigen-specific B cells, including next generation antigen barcoding and an integrated computational framework for B cell multi-omics. We demonstrate the power of this approach by recovering thousands of antigen-specific mAbs, including the efficient isolation of extremely rare precursors of VRC01-class and IOMA-class broadly neutralizing HIV mAbs.
Topics: Antibodies, Neutralizing; B-Lymphocytes; HIV Antibodies; Antigens; Antibodies, Monoclonal; HIV-1
PubMed: 36968243
DOI: 10.3389/fcimb.2022.962945 -
AIDS Reviews 2015Broadly neutralizing antibodies represent the major protective mechanism of vaccines targeting pathogenic microbes in humans and animals. For HIV, broadly neutralizing... (Review)
Review
Broadly neutralizing antibodies represent the major protective mechanism of vaccines targeting pathogenic microbes in humans and animals. For HIV, broadly neutralizing antibodies have also been shown to be protective in experimental animal models. However, despite the identification of a respectable number of broadly neutralizing antibodies from chronically infected HIV-positive persons in recent years, attempts to induce such antibodies by vaccines have generally failed over the last decades. Though unsuccessful in view of achieving a protective vaccine against HIV, many of these studies have contributed significantly to the understanding of the generation of broadly neutralizing antibodies against HIV-1 as well as to the vulnerable sites they target on the surface of the virus. Here we review the most important features of patient-derived broadly neutralizing antibodies, the long and complex B-cell maturation pathways required for their production, and the resulting consequences for vaccine development. We further address characteristics of the epitopes targeted by broadly neutralizing antibodies on the virus surface as well as mechanisms of viral escape. Taken together, the identification of vaccine candidates able to induce broadly neutralizing antibodies against HIV-1 is the major challenge in HIV vaccine development. Mutual coevolution of rationally designed HIV vaccine candidates, with affinity maturation pathways of antibodies they induce upon vaccination, may best mimic the natural situation of chronically HIV-infected patients who are able to generate broadly neutralizing antibodies.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; B-Lymphocytes; Epitopes, B-Lymphocyte; Genetic Variation; HIV Antibodies; HIV Infections; HIV-1; Humans; Immune Evasion
PubMed: 26035168
DOI: No ID Found -
Advances in Immunology 2019Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate... (Review)
Review
Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env glycans are derived from the host and present a formidable challenge for host anti-glycan antibody induction. Anti-glycan antibody induction is challenging because anti-HIV-1 glycan antibodies should recognize Env antigen while not acquiring autoreactivity. Thus, the glycan network on HIV-1 Env is referred to as the glycan shield. Despite the challenges presented by immune recognition of host-derived glycans, neutralizing antibodies capable of binding the glycans on HIV-1 Env can be generated by the host immune system in the setting of HIV-1 infection. In particular, a cluster of high mannose glycans, including an N-linked glycan at position 332, form the high mannose patch and are targeted by a variety of broadly neutralizing antibodies. These high mannose patch-directed HIV-1 antibodies can be categorized into distinct categories based on their antibody paratope structure, neutralization activity, and glycan and peptide reactivity. Below we will compare and contrast each of these classes of HIV-1 glycan-dependent antibodies and describe vaccine design efforts to elicit each of these antibody types.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibody Formation; Broadly Neutralizing Antibodies; Epitopes; Glycosylation; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunogenicity, Vaccine; Mannose; Peptide Fragments; Polysaccharides
PubMed: 31607367
DOI: 10.1016/bs.ai.2019.08.002 -
Current HIV/AIDS Reports Oct 2020The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system... (Review)
Review
PURPOSE OF REVIEW
The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system (CNS). Here we review the most promising immunotherapeutic strategies that can be used to target HIV in the CNS and focus on identifying their potential benefits while exploring the challenges that remain in their application.
RECENT FINDINGS
We have identified five immunotherapeutic strategies that hold potential in managing CNS disease among HIV-infected patients. These include broadly neutralizing antibodies, multi-affinity antibodies, CAR-T cell therapy, checkpoint inhibitors, and therapeutic vaccines. Each class of immunotherapy presents unique mechanisms by which CNS viremia and latency may be addressed but are faced with several challenges. CAR-T cell therapy and multi-affinity antibodies seem to hold promise, but combination therapy is likely to be most effective. However, more human trials are needed before the clinical benefits of these therapies are realized.
Topics: Antibodies, Neutralizing; Central Nervous System; Combined Modality Therapy; HIV Antibodies; HIV Infections; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Viral Vaccines; Viremia
PubMed: 32671567
DOI: 10.1007/s11904-020-00519-w