HIV type 1 (HIV-1) is characterized by its rapid genetic evolution, leading to challenges in anti-HIV therapy. However, the sequence variations in HIV-1 proteins are not randomly distributed due to a combination of functional constraints and genetic drift. In this study, we examined patterns of sequence variability for evidence of linked sequence changes (termed as coevolution or covariation) in 15 HIV-1 proteins. It shows that the percentage of charged residues in the coevolving residues is significantly higher than that in all the HIV-1 proteins. Most of the coevolving residues are spatially proximal in the protein structures and tend to form relatively compact and independent units in the tertiary structures, termed as “protein sectors”. These protein sectors are closely associated with anti-HIV drug resistance, T cell epitopes, and antibody binding sites. Finally, we explored candidate peptide inhibitors based on the protein sectors. Our results can establish an association between the coevolving residues and molecular functions of HIV-1 proteins, and then provide us with valuable knowledge of pathology of HIV-1 and therapeutics development.