SARS-CoV-2 utilizes host cell RNA-binding proteins (RBPs) to carry out many steps of the infectious cycle. At the same time, a number of human RBPs are involved in antiviral immunity. During circulation in the human population, mutations that appeared in the SARS-CoV-2 genome could alter the interaction between cellular RBPs and the virus. Here, we have analyzed the genomes of various SARS-CoV-2 strains, including the Alpha, Delta and Omicron variants, and proposed a model of interactions between RBPs and SARS-CoV-2 RNA. It turned out that, despite the generally accepted opinion about the importance of the RBP‒virus interaction, since the onset of the COVID-19 pandemic there has been a gradual decrease in the affinity of RBPs for SARS-CoV-2 RNA.