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CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection.

ABSTRACT: HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long term control of viral replication. In this study we demonstrate a synergistic interaction between CD8 T cells and bNAbs using an in vitro model. Our data suggest that this combinatorial approach is very effective at suppressing viral replication in vitro and should be considered in future therapeutic studies.

SUBMITTER: Veenhuis RT

PROVIDER: S-EPMC8358597 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection.

Veenhuis Rebecca T RT Garliss Caroline C CC Bailey Justin R JR Blankson Joel N JN

Frontiers in immunology 20210729

HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long t ...[more]

PMID: 34394110

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Project description:The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality.

Project description:IntroductionThe last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.DiscussionRecently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.ConclusionsIterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.

Dataset Information

CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection.

Publications

CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection.

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