Host-directed antivirals remain a promising therapeutic approach for many viruses, including SARS-CoV-2 (CoV2), but development of such interventions requires a deeper understanding of virus-host interactions. Here, we use subcellular proteomics to detect CoV2-induced changes in host protein synthesis networks. We identify molecular chaperones required for CoV2 infection and show that their inhibition reduces infection without major toxicity. We also find that the untranslated regions of CoV2 genomic RNA (gRNA) are inefficient drivers of translation initiation, and that the viral non-structural protein Nsp1 suppresses cellular mRNA but enhances viral gRNA translation. Nsp1 preferentially interacts with pre-initiation complexes containing translation factor EIF1A, which is required for accurate start site selection on CoV2 gRNA. Without EIF1A, more ribosomes initiate translation from an alternative start codon, resulting in lower Orf1 translation and reduced viral titers. Together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and identifies druggable targets for antiviral development.