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Current Opinion in Virology Jun 2022Potent broadly neutralizing antibodies (bNAbs) targeting HIV-1 exhibit significant antiviral activity in humans. Recent advances have demonstrated that novel antibodies... (Review)
Review
Potent broadly neutralizing antibodies (bNAbs) targeting HIV-1 exhibit significant antiviral activity in humans. Recent advances have demonstrated that novel antibodies and bNAb combinations can effectively restrict the development of viral escape mutations. Moreover, passive immunization trials have provided proof-of-principle for bNAb-mediated prevention of infection with antibody-sensitive HIV-1 strains. In contrast, clinical studies investigating the activity of HIV-1 bNAbs on the latent reservoir failed to demonstrate substantial effects. Clinical adoption of HIV-1 bNAbs will require the development of more potent and broadly active antibodies as well as their implementation in optimized strategies to fully harness the capabilities of bNAbs. We review preclinical and clinical studies on HIV-1 bNAbs to highlight their potential and remaining limitations.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 35306354
DOI: 10.1016/j.coviro.2022.101211 -
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 -
Current Opinion in HIV and AIDS Jul 2019Exploring the molecular details of the coevolution of HIV-1 Envelope with broadly neutralizing antibodies (bNAbs) in infected individuals over time provides insights for... (Review)
Review
PURPOSE OF REVIEW
Exploring the molecular details of the coevolution of HIV-1 Envelope with broadly neutralizing antibodies (bNAbs) in infected individuals over time provides insights for vaccine design. Since mid-2017, the number of individuals described in such publications has nearly tripled. New publications have extended such studies to new epitopes on Env and provided more detail on previously known sites.
RECENT FINDINGS
Studies of two donors - one of them an infant, the other with three lineages targeting the same site - has deepened our understanding of V3-glycan-directed lineages. A V2-apex-directed lineage showed remarkable similarity to a lineage from a previously described donor, revealing general principles for this class of bNAbs. Understanding development of CD4 binding site antibodies has been enriched by the study of a VRC01-class lineage. Finally, the membrane-proximal external region is a new addition to the set of epitopes studied in this manner, with early development events explored in a study of three lineages from a single donor.
SUMMARY
These studies provide templates for immunogen design to elicit bNAbs against a widened set of epitopes, generating new directions in the quest for an HIV vaccine.
Topics: Animals; Biological Coevolution; Broadly Neutralizing Antibodies; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 30994504
DOI: 10.1097/COH.0000000000000550 -
Cell Reports Jul 2023Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with...
Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with prefusion-stabilized envelope trimers eliciting autologous neutralizing antibodies has been reported in multiple vaccine-test species, though not in humans. To investigate elicitation of HIV-1 neutralizing antibodies in humans, here, we analyze B cells from a phase I clinical trial of the "DS-SOSIP"-stabilized envelope trimer from strain BG505, identifying two antibodies, N751-2C06.01 and N751-2C09.01 (named for donor-lineage.clone), that neutralize the autologous tier-2 strain, BG505. Though derived from distinct lineages, these antibodies form a reproducible antibody class that targets the HIV-1 fusion peptide. Both antibodies are highly strain specific, which we attribute to their partial recognition of a BG505-specific glycan hole and to their binding requirements for a few BG505-specific residues. Prefusion-stabilized envelope trimers can thus elicit autologous tier-2 neutralizing antibodies in humans, with initially identified neutralizing antibodies recognizing the fusion-peptide site of vulnerability.
Topics: Humans; AIDS Vaccines; Antibodies, Neutralizing; env Gene Products, Human Immunodeficiency Virus; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV-1; Peptides
PubMed: 37436899
DOI: 10.1016/j.celrep.2023.112755 -
Current Opinion in HIV and AIDS Jul 2019Although the goal of preventive HIV vaccine design is primarily the induction of broadly neutralizing antibodies (bNAbs), recent evidence suggests that a protective... (Review)
Review
PURPOSE OF REVIEW
Although the goal of preventive HIV vaccine design is primarily the induction of broadly neutralizing antibodies (bNAbs), recent evidence suggests that a protective response will also benefit from Fc effector functions. Here, we provide an update on the antibody response to HIV infection, including both Fab and Fc-mediated antibody responses. We also highlight recent studies showing the interplay between these functions, focusing primarily on studies published in the last year.
RECENT FINDINGS
Identification and characterization of bNAb donors continues to provide insights into viral factors that are potentially translatable to vaccine design. Improved and more diverse measures of Fc effector function, and modulators thereof, are enabling a deeper understanding of their role in infection. New data providing mechanistic links between the innate and adaptive humoral immune responses are creating exciting opportunities for vaccine strategies, with the aim of eliciting a polyfunctional protective response.
SUMMARY
New insights into the overall humoral response to HIV infection are defining diverse and synergistic mechanisms required for antibody protection from HIV through vaccination.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 31033730
DOI: 10.1097/COH.0000000000000559 -
Cell Reports. Medicine Apr 2023Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is...
Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.
Topics: Mice; Animals; Broadly Neutralizing Antibodies; Antibodies, Neutralizing; HIV-1; HIV Antibodies; HIV Seropositivity; Vaccination
PubMed: 37044090
DOI: 10.1016/j.xcrm.2023.101003 -
Frontiers of Medicine Feb 2020Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy.... (Review)
Review
Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Drug Discovery; Drug Evaluation, Preclinical; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 31858368
DOI: 10.1007/s11684-019-0721-9