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Cell Host & Microbe Jul 2023Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here, we describe a deep mutational...
Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here, we describe a deep mutational scanning system that can measure the effects of combinations of mutations to HIV envelope (Env) on neutralization by antibodies and polyclonal serum. We first show that this system can accurately map how all functionally tolerated mutations to Env affect neutralization by monoclonal antibodies. We then comprehensively map Env mutations that affect neutralization by a set of human polyclonal sera that neutralize diverse strains of HIV and target the site engaging the host receptor CD4. The neutralizing activities of these sera target different epitopes, with most sera having specificities reminiscent of individual characterized monoclonal antibodies, but one serum targeting two epitopes within the CD4-binding site. Mapping the specificity of the neutralizing activity in polyclonal human serum will aid in assessing anti-HIV immune responses to inform prevention strategies.
Topics: Humans; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; Mutation; Epitopes; HIV-1; Antibodies, Monoclonal; HIV Envelope Protein gp120; env Gene Products, Human Immunodeficiency Virus
PubMed: 37327779
DOI: 10.1016/j.chom.2023.05.025 -
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 -
The Journal of Experimental Medicine Sep 2023Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses...
Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses in a cohort of elderly and younger individuals who received mRNA booster vaccinations. Plasma neutralizing potency and breadth were similar between the two groups. By contrast, the absolute number of SARS-CoV-2-specific memory B cells was lower in the elderly. Antibody sequencing revealed that the SARS-CoV-2-specific elderly memory compartments were more clonal and less diverse. Notably, memory antibodies from the elderly preferentially targeted the ACE2-binding site on the RBD, while those from younger individuals targeted less accessible but more conserved epitopes. Nevertheless, individual memory antibodies elicited by booster vaccines in the elderly and younger individuals showed similar levels of neutralizing activity and breadth against SARS-CoV-2 variants. Thus, the relatively diminished protective effects of vaccination against serious disease in the elderly are associated with a smaller number of antigen-specific memory B cells that express altered antibody repertoires.
Topics: Aged; Humans; Memory B Cells; COVID-19; SARS-CoV-2; Vaccination; Antibodies; RNA, Messenger; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37368240
DOI: 10.1084/jem.20230668 -
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 -
Science Translational Medicine Jul 2023Broadly neutralizing antibodies (bNAbs) may provide an alternative to standard antiretroviral treatment (ART) for controlling HIV-1 replication and may have... (Clinical Trial)
Clinical Trial
Broadly neutralizing antibodies (bNAbs) may provide an alternative to standard antiretroviral treatment (ART) for controlling HIV-1 replication and may have immunotherapeutic effects against HIV-1 reservoirs. We conducted a prospective clinical trial with two HIV-1 bNAbs (VRC01LS and 10-1074) in children ( = 25) who had previously initiated small-molecule ART treatment before 7 days of age and who continued treatment for at least 96 weeks. Both bNAbs were dosed intravenously every 4 weeks, overlapping with ART for at least 8 weeks and then continued for up to 24 weeks or until detectable viremia of HIV-1 RNA rose above 400 copies per milliliter in the absence of ART. Eleven (44%) children maintained HIV-1 RNA below 400 copies per milliliter through 24 weeks of bNAb-only treatment; 14 (56%) had detectable viremia above 400 copies per milliliter at a median of 4 weeks. Archived HIV-1 provirus susceptible to 10-1074, lower birth HIV-1 DNA reservoir in peripheral blood mononuclear cells, sustained viral suppression throughout early life, and combined negative qualitative HIV-1 DNA polymerase chain reaction and negative HIV-1 serology at entry were associated with maintaining suppression on bNAbs alone. This proof-of-concept study suggests that bNAbs may represent a promising treatment modality for infants and children living with HIV-1. Future studies using newer bNAb combinations with greater breadth and potency are warranted.
Topics: Child; Humans; Anti-Retroviral Agents; Antibodies, Neutralizing; Botswana; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Leukocytes, Mononuclear; Prospective Studies; Viremia
PubMed: 37406137
DOI: 10.1126/scitranslmed.adh0004 -
Current Opinion in HIV and AIDS Nov 2023There is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we... (Review)
Review
PURPOSE OF REVIEW
There is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we review key qualities of vaccine-elicited CD8 + T cells as well as major CD8 + T cell-based delivery platforms used in recent HIV vaccine clinical trials.
RECENT FINDINGS
Much progress has been made in improving HIV immunogen design and delivery platforms to optimize CD8 + T cell responses. With regards to viral vectors, recent trials have tested newer chimp and human adenovirus vectors as well as a CMV vector. DNA vaccine immunogenicity has been increased by delivering the vaccines by electroporation and together with adjuvants as well as administering them as part of a heterologous regimen. In preclinical models, self-amplifying RNA vaccines can generate durable tissue-based CD8 + T cells. While it may be beneficial for HIV vaccines to recapitulate the functional and phenotypic features of HIV-specific CD8 + T cells isolated from elite controllers, most of these features are not routinely measured in HIV vaccine clinical trials.
SUMMARY
Identifying a vaccine capable of generating durable T cell responses that target mutationally vulnerable epitopes and that can rapidly intercept infecting or rebounding virus remains a challenge for HIV. Comprehensive assessment of HIV vaccine-elicited CD8 + T cells, as well as comparisons between different vaccine platforms, will be critical to advance our understanding of how to design better CD8 + T cell-based vaccines for HIV.
Topics: Humans; AIDS Vaccines; HIV Infections; CD8-Positive T-Lymphocytes; Genetic Vectors; Epitopes
PubMed: 37751362
DOI: 10.1097/COH.0000000000000824 -
Frontiers in Pharmacology 2023The human immunodeficiency virus (HIV) persists in latently infected CD4T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome... (Review)
Review
The human immunodeficiency virus (HIV) persists in latently infected CD4T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome (AIDS) is associated with HIV-1. Possibly, treating HIV/AIDS is an essential but challenging clinical goal. This review provides a detailed account of the types and mechanisms of monotherapy and combination therapy against HIV-1 and describes nanoparticle and hydrogel delivery systems. In particular, the recently developed capsid inhibitor (Lenacapavir) and the Ainuovirine/tenofovir disoproxil fumarate/lamivudine combination (ACC008) are described. It is interestingly to note that the lack of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and the multipass transmembrane proteins serine incorporator 5 (SERINC5) may be one of the reasons for the enhanced infectivity of HIV-1. This discovery of SERINC3 and SERINC5 provides new ideas for HIV-1 medication development. Therefore, we believe that in treating AIDS, antiviral medications should be rationally selected for pre-exposure and post-exposure prophylaxis to avoid the emergence of drug resistance. Attention should be paid to the research and development of new drugs to predict HIV mutations as accurately as possible and to develop immune antibodies to provide multiple guarantees for the cure of AIDS.
PubMed: 37954841
DOI: 10.3389/fphar.2023.1294966 -
Nature Medicine Oct 2023The main barrier to HIV cure is a persistent reservoir of latently infected CD4 T cells harboring replication-competent provirus that fuels rebound viremia upon...
The main barrier to HIV cure is a persistent reservoir of latently infected CD4 T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4 T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure.
Topics: Animals; HIV Infections; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Macaca mulatta; Anti-Retroviral Agents; Virus Latency; Virus Replication; HIV-1; Antibodies; Lymph Nodes; CD4-Positive T-Lymphocytes; Viral Load
PubMed: 37783968
DOI: 10.1038/s41591-023-02570-7 -
Cell Reports Jul 2023Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency...
Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC < 1 μg/mL) and improve median potency (IC) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.
Topics: Humans; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; HIV-1; Broadly Neutralizing Antibodies; Cryoelectron Microscopy; HIV Seropositivity; Neutralization Tests
PubMed: 37436900
DOI: 10.1016/j.celrep.2023.112711 -
Nature Nov 2023Human immunodeficiency virus 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein (Env) to the cell-surface receptor CD4. Although...
Human immunodeficiency virus 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein (Env) to the cell-surface receptor CD4. Although high-resolution structures of Env in a complex with the soluble domains of CD4 have been determined, the binding process is less understood in native membranes. Here we used cryo-electron tomography to monitor Env-CD4 interactions at the membrane-membrane interfaces formed between HIV-1 and CD4-presenting virus-like particles. Env-CD4 complexes organized into clusters and rings, bringing the opposing membranes closer together. Env-CD4 clustering was dependent on capsid maturation. Subtomogram averaging and classification revealed that Env bound to one, two and finally three CD4 molecules, after which Env adopted an open state. Our data indicate that asymmetric HIV-1 Env trimers bound to one and two CD4 molecules are detectable intermediates during virus binding to host cell membranes, which probably has consequences for antibody-mediated immune responses and vaccine immunogen design.
Topics: Humans; AIDS Vaccines; Capsid; CD4 Antigens; Cell Membrane; Cryoelectron Microscopy; Electron Microscope Tomography; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Protein Multimerization; Virion
PubMed: 37993716
DOI: 10.1038/s41586-023-06762-6