Clearing HIV-1-infected cells in vivo will be a key component of any approach to provide functional or true cure of HIV-1 infection. The best-defined arm of immunity for killing infected cells is CD8+ cytotoxic T lymphocytes (CTLs), which recognize short viral sequences presented on Human Leukocyte Antigen Class I molecules on infected cell surfaces. However, HIV-1 displays massive mutation and plasticity of its sequences, which limits the efficacy of CTLs in most circumstances. This project is a detailed dissection of the virologic and immunologic factors underlying the ability of HIV-1 to evade CTLs. It explores the constraints imposed on the virus and the immune receptors imposing those constraints. The constraints associated with protective versus non-protective CTL responses are compared, as well as the constraints associated with natural infection versus vaccine-generated anti-HIV-1 CTLs. Specifically, we propose: To define CTL "epitope escape spaces" for protective and non-protective responses to HIV-1, and To compare TCR properties and HIV-1 escape spaces in natural infection to those elicited by a clonal vaccine.