Mapping mutational effects along the evolutionary landscape of HIV envelope

Area of Science:

• Virology
• Evolutionary Biology
• Molecular Biology

Background:

• The evolutionary trajectory of viruses like HIV is constrained by the fitness effects of mutations.
• Understanding how these mutational effects change over time is crucial for predicting viral evolution.
• The prevalence and drivers of shifts in mutational effects within viral proteins are not well understood.

Purpose of the Study:

• To quantify the impact of all possible single amino acid mutations on the growth of two distinct HIV envelope (Env) proteins.
• To determine the extent to which mutational effects are conserved or shift between moderately diverged viral strains.
• To investigate the relationship between site-specific substitutions and shifts in mutational tolerance.

Main Methods:

• Systematic mutagenesis was employed to introduce all single amino acid changes into two HIV Env proteins differing by approximately 100 residues.
• Viral growth assays were used to measure the fitness consequences of each mutation.
• Comparative analysis was performed to identify mutations with differing effects between the two Env proteins.

Main Results:

• Most mutations exhibited similar effects on viral growth across both HIV Env proteins.
• A minority of sites demonstrated significant shifts in amino acid preferences between the two Envs.
• These shifts were not strongly associated with sites that had undergone substitutions and often occurred at non-contact residues, suggesting long-range epistasis.

Conclusions:

• Long-range epistasis can unpredictably alter HIV Env's mutational tolerance during evolution.
• While most site preferences are conserved between moderately diverged HIV strains, shifts can occur, impacting evolutionary pathways.
• These findings highlight the complex interplay of epistasis and mutation in shaping viral evolution.