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Cell Host & Microbe Jun 2021One barrier to HIV-1 eradication is the viral Env protein that is invisible to most antibodies. In this issue of Cell Host & Microbe, Rajashekar et al. (2021) remove...
One barrier to HIV-1 eradication is the viral Env protein that is invisible to most antibodies. In this issue of Cell Host & Microbe, Rajashekar et al. (2021) remove the "invisibility cloak" from Env, make it accessible to antibodies, and demonstrate NK-mediated in vivo killing of infected cells by human plasma antibodies.
Topics: Animals; Antibody-Dependent Cell Cytotoxicity; CD4-Positive T-Lymphocytes; HIV Antibodies; HIV Infections; HIV-1; Humans; Mice; Natural Killer T-Cells; env Gene Products, Human Immunodeficiency Virus
PubMed: 34111390
DOI: 10.1016/j.chom.2021.05.003 -
Current Opinion in HIV and AIDS Jul 2023The discovery of broadly neutralizing HIV-1 antibodies (bNAbs) has provided a framework for vaccine design and created new hope toward an HIV-1 cure. These antibodies... (Review)
Review
PURPOSE OF REVIEW
The discovery of broadly neutralizing HIV-1 antibodies (bNAbs) has provided a framework for vaccine design and created new hope toward an HIV-1 cure. These antibodies recognize the HIV-1 Envelope and inhibit viral fusion with unprecedented breadth and potency. Beyond their unique neutralization capacity, bNAbs also activate immune cells and interfere with viral spread through nonneutralizing activities. Here, we review the landscape of bNAbs functions and their contribution to clinical efficacy.
RECENT FINDINGS
Parallel evaluation of bNAbs nonneutralizing activities using in vivo and in vitro models have revealed how their importance varies across antibodies and strains. Nonneutralizing bNAbs functions target both infected cells and viral particles, leading to their destruction through various mechanisms. Reservoir targeting and prevention in context of suboptimal neutralization highly depends on bNAbs polyfunctionality. We recently showed that bNAbs tether virions at the surface of infected cells, impairing release and forming immune complexes, with consequences that are still to be understood.
SUMMARY
Nonneutralizing activities of bNAbs target infected cells, virions, and immune complexes, promoting viral clearance and possibly improving immune responses. We review how these functions participate to the efficacy of bNAbs and how they can be manipulated to improve bNAbs therapies.
Topics: Humans; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; Antibodies, Neutralizing; HIV-1; Antigen-Antibody Complex
PubMed: 37249912
DOI: 10.1097/COH.0000000000000799 -
Viruses Oct 2020HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1... (Review)
Review
HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have taken place, although some studies suggest access to MPER in the close to native Env conformation. We summarize the data on the structure and function of neutralizing antibodies targeting gp41 HR1, FP and MPER and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env. We further discuss MPER bnAb binding to lipids and the role of somatic mutations in recognizing a bipartite epitope composed of the conserved MPER sequence and membrane components. The problematic of gp41 HR1 access and MPER bnAb auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Epitopes; HIV Antibodies; HIV Envelope Protein gp41; HIV-1; Humans; Mice; Mutation
PubMed: 33114242
DOI: 10.3390/v12111210 -
Current Opinion in HIV and AIDS Jul 2019In the absence of a protective vaccine against HIV-1, passive immunization using novel broadly neutralizing antibodies (bNAbs) is an attractive concept for HIV-1... (Review)
Review
PURPOSE OF REVIEW
In the absence of a protective vaccine against HIV-1, passive immunization using novel broadly neutralizing antibodies (bNAbs) is an attractive concept for HIV-1 prevention. Here, we summarize the results of preclinical and clinical studies of bNAbs, discuss strategies for optimizing bNAb efficacy and lay out current pathways for the development of bNAbs as prophylaxis.
RECENT FINDINGS
Passive transfer of second-generation bNAbs results inpotent protection against infection in preclinical animal models. Furthermore, multiple bNAbs targeting different epitopes on the HIV-1 envelope trimer are in clinical evaluation and have demonstrated favorable safety profiles and robust antiviral activity in chronically infected individuals. The confirmation that passive immunization with bNAb(s) will prevent HIV-1 acquisition in humans is pending and the focus of ongoing investigations. Given the global diversity of HIV-1, bNAb combinations or multispecific antibodies will most likely be required to produce the necessary breadth for effective protection.
SUMMARY
Encouraging results from preclinical and clinical studies support the development of bNAbs for prevention and a number of antibodies with exceptional breadth and potency are available for clinical evaluation. Further optimization of viral coverage and antibody half-life will accelerate the clinical implementation of bNAbs as a critical tool for HIV-1 prevention strategies.
Topics: Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization, Passive
PubMed: 31082819
DOI: 10.1097/COH.0000000000000556 -
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 -
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 -
Nature Medicine Nov 2023Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting...
Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4 T cell counts <200 µl, being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.
Topics: Humans; HIV-1; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; AIDS Vaccines; Virus Replication
PubMed: 37957379
DOI: 10.1038/s41591-023-02582-3 -
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 -
International Journal of Antimicrobial... Dec 2020Antibody-based strategies have been introduced for a number of disease states, but represent a novel approach in the management of human immunodeficiency virus (HIV).... (Review)
Review
Antibody-based strategies have been introduced for a number of disease states, but represent a novel approach in the management of human immunodeficiency virus (HIV). Ibalizumab and leronlimab are monoclonal antibodies with unique mechanisms as a CD4-directed post-attachment inhibitor and a C-C chemokine receptor type 5-directed inhibitor, respectively. These antibody-based strategies are generally well tolerated, have a favourable pharmacokinetic profile allowing for less-frequent dosing, and have a high barrier to resistance. Ibalizumab is currently approved by the US Food and Drug Administration (US FDA) for management of multi-drug-resistant (MDR) HIV infection in patients who are failing their current regimens. Clinical data demonstrated impressive antiretroviral activity with ibalizumab among a complex HIV population in combination with an optimized background regimen, where limited therapeutic options exist. To date, leronlimab has not been granted approval by the US FDA, but has been designated fast-track status. Leronlimab is being studied as a maintenance monotherapy agent in virologically suppressed patients, as well as for treatment of MDR HIV infection in patients who are failing their current regimens. Currently available data in both of these potential areas appear promising for leronlimab. The mechanism of action, pharmacokinetic profile, efficacy and safety of these novel antibody-based strategies represent an advance in the management of HIV. Future studies and post-marketing experience will further determine longer-term clinical efficacy, safety and resistance data for ibalizumab and leronlimab.
Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; CD4 Antigens; Drug Resistance, Viral; HIV Antibodies; HIV Infections; HIV-1; Humans; Receptors, CCR5
PubMed: 33045349
DOI: 10.1016/j.ijantimicag.2020.106186 -
Frontiers in Immunology 2021Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies... (Review)
Review
Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies (bnAbs) to block acquisition of HIV-1 are being rigorously pursued in the clinical setting. bnAbs have demonstrated robust protection in preclinical animal models, and several leading bnAb candidates have shown favorable safety and pharmacokinetic profiles when tested individually or in combinations in early phase human clinical trials. Furthermore, passive administration of bnAbs in HIV-1 infected individuals has resulted in prolonged suppression of viral rebound following interruption of combination antiretroviral therapy, and robust antiviral activity when administered to viremic individuals. Recent results from the first efficacy trials testing repeated intravenous administrations of the anti-CD4 binding site bnAb VRC01 have demonstrated positive proof of concept that bnAb passive immunization can confer protection against HIV-1 infection in humans, but have also highlighted the considerable barriers that remain for such strategies to effectively contribute to control of the epidemic. In this review, we discuss the current status of clinical studies evaluating bnAbs for HIV-1 prevention, highlight lessons learned from the recent Antibody Mediated Prevention (AMP) efficacy trials, and provide an overview of strategies being employed to improve the breadth, potency, and durability of antiviral protection.
Topics: Animals; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; CD4 Antigens; Clinical Trials, Phase I as Topic; Epidemics; Forecasting; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization, Passive; Immunoglobulin Fab Fragments; Immunoglobulin Fc Fragments; Male; Models, Animal; Primates; Receptors, Virus
PubMed: 34354713
DOI: 10.3389/fimmu.2021.712122