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Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities.

ABSTRACT: Combination antiretroviral therapy (cART) is effective but not curative, and no successful vaccine is currently available for human immunodeficiency virus-1 (HIV-1). Broadly neutralizing antibodies (bNAbs) provide a new approach to HIV-1 prevention and treatment, and these promising candidates advancing into clinical trials have shown certain efficacies in infected individuals. In addition, bNAbs have the potential to kill HIV-1-infected cells and to affect the course of HIV-1 infection by directly engaging host immunity. Nonetheless, challenges accompany the use of bNAbs, including transient suppression of viraemia, frequent emergence of resistant viruses in rebound viraemia, suboptimal efficacy in virus cell-to-cell transmission, and unclear effects on the cell-associated HIV-1 reservoir. In this review, we discuss opportunities and potential strategies to address current challenges to promote the future use of immunotherapy regimens.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7040474 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities.

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