Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution

Area of Science:

• Virology
• Molecular Evolution
• Biochemistry

Background:

• HIV-1 protein sequence evolution is influenced by mutation, genetic code, and fitness.
• Interdependence of these factors complicates direct inference from phylogenetic data.

Purpose of the Study:

• Investigate HIV-1 protein sequence evolution by experimentally determining the fitness landscape of protease amino acid changes.
• Compare experimental fitness data with observed protease variant frequencies in drug-naïve individuals.

Main Methods:

• Constructed an experimental fitness landscape for all individual amino acid substitutions in HIV-1 protease.
• Analyzed a dataset of 32,163 HIV-1 protease sequences from drug-naïve individuals.
• Correlated experimental fitness with in vivo variant frequencies and mutational accessibility.

Main Results:

• Commonly observed amino acids in isolates exhibited robust experimental fitness, validating the fitness landscape.
• Amino acid changes requiring multiple mutations showed slightly lower fitness, aligning with the genetic code's preference for conservative changes.
• Prevalent multiple-base mutations in isolates were often accessible via intermediate single mutations with high fitness, suggesting mutational sampling influences their occurrence.

Conclusions:

• Experimental fitness landscapes accurately reflect selection pressures on HIV-1 protease in vivo.
• The genetic code and mutational accessibility significantly influence HIV-1 protease evolution.
• Mutational sampling plays a critical role in the prevalence of multiple-base mutations in HIV-1 protease sequences.