Human immunodeficiency virus (HIV) carries abundant human cell proteins, particularly human leukocyte antigen (HLA) molecules when the virus leaves host cells. Immunization in macaques with HLAs protects the animals from simian immunodeficiency virus infection. This finding offers an alternative approach to the development of HLA molecule-based HIV vaccines. Decades of studies have enhanced a great deal of our understanding of the mechanisms of allo-immune response-mediated anti-HIV immunity. These include cell-mediated immunity, innate immunity, and antibody response. These studies provided a rationale for the future design of effective HIV vaccines.