University of Massachusetts Medical School Faculty Publications


Constrained mutational sampling of amino acids in HIV-1 protease evolution

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Department of Medicine; Program in Bioinformatics and Integrative Biology; Program in Molecular Medicine; Schiffer Lab

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Ecology and Evolutionary Biology | Genetic Phenomena | Genetics and Genomics | Nucleic Acids, Nucleotides, and Nucleosides | Viruses


The evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on protein sequence evolution are interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. We compared our experimental results to the frequency of protease variants in a publicly available dataset of 32,163 sequenced isolates from drug-naive individuals. The most common amino acids in sequenced isolates supported robust experimental fitness, indicating that the experimental fitness landscape captured key features of selection acting on protease during viral infections of hosts. Amino acid changes requiring multiple mutations from the likely ancestor were slightly less likely to support robust experimental fitness than single mutations, consistent with the genetic code favoring chemically conservative amino acid changes. Amino acids that were common in sequenced isolates were predominantly accessible by single mutations from the likely protease ancestor. Multiple mutations commonly observed in isolates were accessible by mutational walks with highly fit single mutation intermediates. Our results indicate that the prevalence of multiple base mutations in HIV-1 protease is strongly influenced by mutational sampling.


fitness landscape, mutation, HIV

DOI of Published Version



Mol Biol Evol. 2019 Feb 4. pii: 5306343. doi: 10.1093/molbev/msz022. [Epub ahead of print] Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Molecular biology and evolution

PubMed ID