Significance Simian–human immunodeficiency viruses (SHIVs) are an invaluable tool for assessing HIV-1 vaccines, developing therapeutic “cure” strategies, and understanding viral immunopathogenesis. However, only limited success has been achieved in creating SHIVs that incorporate HIV-1 envelopes (Envs) that retain the antigenic features of clinically relevant viruses. Here we focus on a critical residue of the CD4-binding region, Env375, which is under strong positive selection across the broad range of primate lentiviruses. We find that genotypic variation of residue 375 allows for the creation of pathogenic SHIVs that retain the antigenicity, tier 2 neutralization sensitivity, and persistence properties characteristic of primary HIV-1 strains. Taken together, our findings suggest a new paradigm for SHIV design and modeling with important applications to HIV-1 vaccine, cure, and pathogenesis research.