Friend virus infection of adult immunocompetent mice is a well established model for studying genetic resistance to infection by an immunosuppressive retrovirus. This paper reviews both the genetics of immune resistance and the types of immune responses required for recovery from infection. Specific major histocompatibility complex (MHC) class I and II alleles are necessary for recovery, as is a non-MHC gene, Rfv-3, which controls virus-specific antibody responses. In concordance with these genetic requirements are immunological requirements for cytotoxic T lymphocyte, T helper, and antibody responses, each of which provides essential nonoverlapping functions. The complexity of responses necessary for recovery from Friend virus infection has implications for both immunotherapies and vaccines. For example, it is shown that successful passive antibody therapy is dependent on MHC type because of the requirement for T cell responses. For vaccines, successful immunization requires priming of both T cell and B cell responses. In vivo depletion experiments demonstrate different requirements for CD8 ؉ T cells depending on the vaccine used. The implications of these studies for human retroviral diseases are discussed.Scientific knowledge of retroviral infections in humans is relatively new and little is known about the types of immune responses required to successfully defend against these infections. Such knowledge would be extremely valuable for designing vaccines and immunomodulatory therapeutics. Studies of long term survivors of HIV infection are beginning to provide some insights (1-6), but such individuals are rare, and data are difficult to obtain. In general, cell-mediated responses rather than antibodies are considered the critical elements responsible for resolving most human viral infections. This is because humans with genetic deficiencies in T lymphocytes are very susceptible to many viral infections whereas those with antibody deficiencies are not (7,8). However, antibody responses also appear essential for resistance against certain viruses such as enterovirus (9) and rabies virus (10), and there are numerous examples of antibodies curing or preventing viral infections (11-17). Thus, there remains controversy regarding which arms of the specific immune system are most important for resolving viral infections. Most likely this resolution depends on the specific virus and host involved, and often more than one aspect of the immune response is important, if not essential.This review summarizes studies from the polycythemiainducing strain of Friend virus (FV) complex, an immunosuppressive retrovirus model that induces leukemia in mice. The results indicate that resolution of retroviral infections may require more complex immunological responses than have been found for most other viruses. Numerous experiments using both genetic and immunological approaches demonstrate that immune resistance to FV requires multiple arms of the immune system, including CD4 ϩ T cells, CD8 ϩ T cells, and B cells, each pro...