Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1
- Max Planck Institute for Dynamics and Self-Organization, Germany
- University of Cologne, Germany
- University of Washington, United States
Abstract
Infusion of broadly neutralizing antibodies (bNAbs) has shown promise as an alternative to anti-retroviral therapy against HIV. A key challenge is to suppress viral escape, which is more effectively achieved with a combination of bNAbs. Here, we propose a computational approach to predict the efficacy of a bNAb therapy based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we predict the distribution of rebound times in three clinical trials. We show that a cocktail of three bNAbs is necessary to effectively suppress viral escape, and predict the optimal composition of such bNAb cocktail. Our results offer a rational therapy design for HIV, and show how genetic data can be used to predict treatment outcomes and design new approaches to pathogenic control.
Data availability
The current manuscript is a computational study, so no data have been generated for this manuscript. Reference to the previously published data used in this manuscript is provided. Modelling code is uploaded on GitHub at https://github.com/StatPhysBio/HIVTreatmentOptimization, and in the Julia package https://github.com/StatPhysBio/EscapeSimulator.
-
Project: PRJEB9618European Nucleotide Archive, Accession no: PRJEB9618.
-
HIV-1 isolate 2A1_DB7_02 from USA envelope glycoprotein (env) gene, partial cdsGeneBank, accession no: KX016803.
-
Antibody 10-1074 suppresses viremia in HIV-1-infected individualsGeneBank, accession no: KY323724-KY324834.
-
Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individualsGeneBank, accession no: MH632763 - MH633255.
Article and author information
Author details
Armita Nourmohammad
Funding
Deutsche Forschungsgemeinschaft (1310)
- Armita Nourmohammad
National Science Foundation (2045054)
- Armita Nourmohammad
1Max Planck Institute for Dynamics and Self-organization (open access funding)
- Colin LaMont
- Jakub Otwinowski
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kayla Sprenger, MIT
Version history
- Received: December 1, 2021
- Preprint posted: December 5, 2021 (view preprint)
- Accepted: July 4, 2022
- Accepted Manuscript published: July 19, 2022 (version 1)
- Version of Record published: September 12, 2022 (version 2)
Copyright
© 2022, LaMont et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,646
- views
-
- 523
- downloads
-
- 15
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1
eLife 11:e76004.
https://doi.org/10.7554/eLife.76004
Further reading
-
- Evolutionary Biology
Extant ecdysozoans (moulting animals) are represented by a great variety of soft-bodied or articulated organisms that may or may not have appendages. However, controversies remain about the vermiform nature (i.e. elongated and tubular) of their ancestral body plan. We describe here Beretella spinosa gen. et sp. nov. a tiny (maximal length 3 mm) ecdysozoan from the lowermost Cambrian, Yanjiahe Formation, South China, characterized by an unusual sack-like appearance, single opening, and spiny ornament. Beretella spinosa gen. et sp. nov has no equivalent among animals, except Saccorhytus coronarius, also from the basal Cambrian. Phylogenetic analyses resolve both fossil species as a sister group (Saccorhytida) to all known Ecdysozoa, thus suggesting that ancestral ecdysozoans may have been non-vermiform animals. Saccorhytids are likely to represent an early off-shot along the stem-line Ecdysozoa. Although it became extinct during the Cambrian, this animal lineage provides precious insight into the early evolution of Ecdysozoa and the nature of the earliest representatives of the group.
-
- Biochemistry and Chemical Biology
- Evolutionary Biology
The emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely unexplored for membrane transporters, even though the ability to acquire new nutrients from a changing environment requires evolvability of transport functions. Here, we demonstrate the importance of environmental pressure in obtaining a new activity or altering a promiscuous activity in members of the amino acid-polyamine-organocation (APC)-type yeast amino acid transporters family. We identify APC members that have broader substrate spectra than previously described. Using in vivo experimental evolution, we evolve two of these transporter genes, AGP1 and PUT4, toward new substrate specificities. Single mutations on these transporters are found to be sufficient for expanding the substrate range of the proteins, while retaining the capacity to transport all original substrates. Nonetheless, each adaptive mutation comes with a distinct effect on the fitness for each of the original substrates, illustrating a trade-off between the ancestral and evolved functions. Collectively, our findings reveal how substrate-adaptive mutations in membrane transporters contribute to fitness and provide insights into how organisms can use transporter evolution to explore new ecological niches.
