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Experimental Biology and Medicine... May 2021Human immunodeficiency virus 1 (HIV-1) infection remains a public health concern globally. Although great strides in the management of HIV-1 have been achieved, current... (Review)
Review
Human immunodeficiency virus 1 (HIV-1) infection remains a public health concern globally. Although great strides in the management of HIV-1 have been achieved, current highly active antiretroviral therapy is limited by multidrug resistance, prolonged use-related effects, and inability to purge the HIV-1 latent pool. Even though novel therapeutic options with HIV-1 broadly neutralizing antibodies (bNAbs) are being explored, the scalability of bNAbs is limited by economic cost of production and obligatory requirement for parenteral administration. However, these limitations can be addressed by antibody mimetics/peptidomimetics of HIV-1 bNAbs. In this review we discuss the limitations of HIV-1 bNAbs as HIV-1 entry inhibitors and explore the potential therapeutic use of antibody mimetics/peptidomimetics of HIV-1 entry inhibitors as an alternative for HIV-1 bNAbs. We highlight the reduced cost of production, high specificity, and oral bioavailability of peptidomimetics compared to bNAbs to demonstrate their suitability as candidates for novel HIV-1 therapy and conclude with some perspectives on future research toward HIV-1 novel drug discovery.
Topics: Anti-HIV Agents; Broadly Neutralizing Antibodies; Drug Discovery; HIV Antibodies; HIV Infections; HIV-1; Humans; Peptidomimetics; Virus Internalization
PubMed: 33596698
DOI: 10.1177/1535370221990870 -
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 -
Current Opinion in HIV and AIDS Jul 2023Successful HIV-1 prevention and therapy will require broad and potent coverage of within-host and global viral diversity. Broadly neutralizing antibody (bNAb)... (Review)
Review
PURPOSE OF REVIEW
Successful HIV-1 prevention and therapy will require broad and potent coverage of within-host and global viral diversity. Broadly neutralizing antibody (bNAb) combination and multispecific therapeutics provide an opportunity to meet this challenge due to the complementary activity of individual antibody components. Here, we review the principles and applications of this concept.
RECENT FINDINGS
The Antibody Mediated Prevention (AMP) trials have demonstrated the high bar for neutralization potency and breadth that bNAb-mediated prevention modalities will need to achieve to have a meaningful impact on the HIV-1 epidemic. Additional clinical studies have recently shown that an even higher bar may be required for therapeutic inhibition of the diverse within-host quasispecies present in viremic and aviremic people with HIV-1 (PWH). We discuss how the complementarity of bNAbs in terms of neutralization profiles, resistance mutations and coverage of within-host quasispecies may overcome these stringent requirements and lead to effective bNAb combination or multispecific antibody based prophylactic and therapeutic strategies.
SUMMARY
The design of next-generation bNAb-based combination or multispecific therapeutics for the prevention and/or treatment of HIV-1 infection will need to leverage the complementarity of component bNAbs to maximize the potency and breadth that will be required for clinical success.
Topics: Humans; HIV Infections; Broadly Neutralizing Antibodies; HIV Antibodies; HIV-1; Antibodies, Neutralizing
PubMed: 37249911
DOI: 10.1097/COH.0000000000000800 -
Cell Reports Feb 2023Despite prolific efforts to characterize the antibody response to human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) mono-infections, the response...
Despite prolific efforts to characterize the antibody response to human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) mono-infections, the response to chronic co-infection with these two ever-evolving viruses is poorly understood. Here, we investigate the antibody repertoire of a chronically HIV-1/HCV co-infected individual using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq). We identify five HIV-1/HCV cross-reactive antibodies demonstrating binding and functional cross-reactivity between HIV-1 and HCV envelope glycoproteins. All five antibodies show exceptional HCV neutralization breadth and effector functions against both HIV-1 and HCV. One antibody, mAb688, also cross-reacts with influenza and coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examine the development of these antibodies using next-generation sequencing analysis and lineage tracing and find that somatic hypermutation established and enhanced this reactivity. These antibodies provide a potential future direction for therapeutic and vaccine development against current and emerging infectious diseases. More broadly, chronic co-infection represents a complex immunological challenge that can provide insights into the fundamental rules that underly antibody-antigen specificity.
Topics: Humans; Hepacivirus; HIV-1; Coinfection; HIV Infections; Antibodies, Neutralizing; COVID-19; SARS-CoV-2; HIV Antibodies; Hepatitis C
PubMed: 36708513
DOI: 10.1016/j.celrep.2023.112044 -
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 -
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 -
The New England Journal of Medicine Mar 2021Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear.
METHODS
We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC) of acquired isolates was measured with the TZM-bl assay.
RESULTS
Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates.
CONCLUSIONS
VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).
Topics: Adolescent; Adult; Africa South of the Sahara; Americas; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Double-Blind Method; Europe; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; Incidence; Male; Proof of Concept Study; Young Adult
PubMed: 33730454
DOI: 10.1056/NEJMoa2031738 -
Cell Reports Nov 2022Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of...
Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to "open" Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.
Topics: Animals; Humans; Mice; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV-1
PubMed: 36351384
DOI: 10.1016/j.celrep.2022.111624 -
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