The purpose of this proposal is to examine the relationship between the Acquired Immuno-Deficiency Syndrome (AIDS) and the absence of functional immunoregulatory cells in these patients. One way in which this syndrome manifests itself is through infection by a number of pathogens, the most common being that of Pneumocystis carinii, a protozoan resulting in severe penumonia. Another major group manifests itself as Kaposi's sarcoma, and a few cases have developed lymphoma. The majority of patients who have developed the AID syndrome have been homosexuals, very active sexually. Additional patients have been users of intravenous drugs, i.e., heroin, hemophiliacs with a high Factor VIII requirement, and Haitian immigrants. The common denominator in all these patients appears to be profound state of an acquired immunosuppression selective for T cell mediated immune functions, in contrast to humoral immunity which appears to be intact. Our approach to understanding the mechanism of this disorder was to consider the possibility that the primary defect in AIDS was an aberration in functional immunoregulatory cells, resulting, either in the indiscriminate killing of, or the lack of killing of target cells altered by pathogens. In the latter alternative, cell destruction would be due to unchecked proliferation of the infectious agent. Using this approach we have found that symptomatic homosexuals and patients with AIDS have a significantly diminished autologous mixed lymphocyte reaction (AMLR). The absence of the T cell mediated AMLR in these patients was accompanied by an inability of their T lymphocytes to produce interleukin-2 (IL-2), a T cell growth factor. Significantly, the addition of IL-2 to AMLR cultures induces normalization of the low T cell proliferative response. Since immunoregulatory cells, normally generated in the AMLR, induce the differentiation of prekiller to killer T cells, in their absence there could be defective killing of pathogen infected target cells. It is our intention to determine whether the low AMLR and/or lack of regulatory cells is due to deficiency of IL-2, and if these abnormalities are correctable by IL-2. These findings would not only elucidate the pathophysiology of AIDS, but could, in addition, provide an effective treatment modality in a disease with a very high mortality rate.