Efforts to control HIV infection have led to the development of several antiretroviral drugs that can limit virus replication, however, these therapies do not offer a long-term solution to the infection. We can learn a great deal from HIV-infected individuals who have lived for more than ten years and remain healthy without receiving antiviral drugs. These long-term survivors or long-term non-progressors have an immune system that can control HIV infection. A major component of this immune response is innate immunity, particularly the CD8⁺ cell antiviral non-cytotoxic response (CNAR), mediated by a novel CD8⁺ cell antiviral factor (CAF). The characteristics of CNAR and CAF will be described and progress made toward identifying CAF will be reviewed. These studies have uncovered several potentially important natural anti-HIV factors and their relationship to the originally described CAF is considered.