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.
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.
- Armita Nourmohammad
- Armita Nourmohammad
- 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.
- Kayla Sprenger, MIT
- Received: December 1, 2021
- Accepted: July 4, 2022
- Accepted Manuscript published: July 19, 2022 (version 1)
© 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.
The Early Cretaceous diversification of birds was a major event in the history of terrestrial ecosystems, occurring during the earliest phase of the Cretaceous Terrestrial Revolution, long before the origin of the bird crown-group. Frugivorous birds play an important role in seed dispersal today. However, evidence of fruit consumption in early birds from outside the crown-group has been lacking. Jeholornis is one of the earliest-diverging birds, only slightly more crownward than Archaeopteryx, but its cranial anatomy has been poorly understood, limiting trophic information which may be gleaned from the skull. Originally hypothesised to be granivorous based on seeds preserved as gut contents, this interpretation has become controversial. We conducted high-resolution synchrotron tomography on an exquisitely preserved new skull of Jeholornis, revealing remarkable cranial plesiomorphies combined with a specialised rostrum. We use this to provide a near-complete cranial reconstruction of Jeholornis, and exclude the possibility that Jeholornis was granivorous, based on morphometric analyses of the mandible (3D) and cranium (2D), and comparisons with the 3D alimentary contents of extant birds. We show that Jeholornis provides the earliest evidence for fruit consumption in birds, and indicates that birds may have been recruited for seed dispersal during the earliest stages of the avian radiation. As mobile seed dispersers, early frugivorous birds could have expanded the scope for biotic dispersal in plants, and might therefore explain, at least in part, the subsequent evolutionary expansion of fruits, indicating a potential role of bird–plant interactions in the Cretaceous Terrestrial Revolution.
Assembly pathways of protein complexes should be precise and efficient to minimise misfolding and unwanted interactions with other proteins in the cell. One way to achieve this efficiency is by seeding assembly pathways during translation via the cotranslational assembly of subunits. While recent evidence suggests that such cotranslational assembly is widespread, little is known about the properties of protein complexes associated with the phenomenon. Here, using a combination of proteome-specific protein complex structures and publicly available ribosome profiling data, we show that cotranslational assembly is particularly common between subunits that form large intermolecular interfaces. To test whether large interfaces have evolved to promote cotranslational assembly, as opposed to cotranslational assembly being a non-adaptive consequence of large interfaces, we compared the sizes of first and last translated interfaces of heteromeric subunits in bacterial, yeast, and human complexes. When considering all together, we observe the N-terminal interface to be larger than the C-terminal interface 54% of the time, increasing to 64% when we exclude subunits with only small interfaces, which are unlikely to cotranslationally assemble. This strongly suggests that large interfaces have evolved as a means to maximise the chance of successful cotranslational subunit binding.