(A) In the study reported in this issue of the JCI by Aurora et al. (8), patients were grouped according to their treatment response. The sequences of the complete HCV open reading frame obtained from each group of patients prior to treatment were aligned and analyzed for covariance. An example covariant pair is shown in each alignment (red arrows). The set of all covariant pairs forms a network in which each node is an amino acid position and each connecting line represents covariance between 2 positions. The networks differ by treatment response class and may be used to generate markers indicative of HCV treatment outcome. (B) Various causes of covariance in HCV (red arrows). (i) Phylogenetic covariance is an artifact of a shared ancestry, but does not reflect any functional relationship. (ii) RNA secondary structure gives rise to nucleotide-level covariance. (iii) Protein-protein interaction residues covary. (iv) Intraprotein covariance may indicate direct residue contact or indirect interaction through the protein. (v) Variation in a shared interaction partner (host or viral) may result in coordinated variation in a pair of residues. (vi) MHC epitopes will covary across hosts with different HLA alleles.