ArticleProceedings of the National Academy of Sciences of the United States of America2011
Coordinate linkage of HIV evolution reveals regions of immunological vulnerability.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers.
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Who cites it
112 citing papers in PubMed, 202 citations in OpenAlex.
- HIV-1 amino acid changes among participants with virologic failure: associations with first-line efavirenz or atazanavir plus ritonavir and disease status.The Journal of infectious diseases · 2012Trial
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- Polymorphic residues in HLA-B that mediate HIV control distinctly modulate peptide interactions with both TCR and KIR molecules.Structure (London, England : 1993) · 2024Article
- Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis.Nature communications · 2023Article
- HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies.Virus evolution · 2023Article
- Understanding the mutational frequency in SARS-CoV-2 proteome using structural features.Computers in biology and medicine · 2022Article
- Correlations from structure and phylogeny combine constructively in the inference of protein partners from sequences.PLoS computational biology · 2022Article
- Inferring the intrinsic mutational fitness landscape of influenzalike evolving antigens from temporally ordered sequence data.Physical review. E · 2022Article
- Epistatic models predict mutable sites in SARS-CoV-2 proteins and epitopes.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Evolutionary modeling reveals enhanced mutational flexibility of HCV subtype 1b compared with 1a.iScience · 2022Article
- Phase separation in fluids with many interacting components.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Genome-wide covariation in SARS-CoV-2.Mathematical biosciences · 2021Article
- CD8 T Cell Vaccines and a Cytomegalovirus-Based Vector Approach.Life (Basel, Switzerland) · 2021Review
- Article
- In silico T cell epitope identification for SARS-CoV-2: Progress and perspectives.Advanced drug delivery reviews · 2021Review
- Asymptotics of eigenstructure of sample correlation matrices for high-dimensional spiked models.Statistica Sinica · 2021Article
52 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 6 institutions in 4 countries.
Funding
Abstract
Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.