IMMUNOPATHOLOGY OF LYMPHOID NEOPLASIA IN AIDS

The objectives of this research proposal are 1) to characterize the natural clinical history and the biological features of the "pre- malignant" conditions and the malignant lymphoid neoplasms which occur in association with the Acquired Immune Deficiency Syndrome (AIDS) and the AIDS-related complex (ARC); and 2) to determine the pathogenetic interrelationships between these benign and malignant lymphoid porliferations. These objectives will be accomplished primarily by molecular genetic investigations utilizing the expression and patterns of rearrangement of immunoglobulin and T cell receptor (T alpha, T beta, T alpha) genes as markers of lineage, clonality and differentiation in the B and T cell lineages, respectively, and the patterns of expression of certain proto-oncogenes as markers of the proliferative and differentiation status of the neoplastic lymphoid cells. The results of these molecular genetic analyses will be correlated with the clinical status and course of each patient and with the morphologic, immunophenotypic and functional characteristics of the neoplastic lymphoid cells obtained from the same lymphoid neoplasms. Specifically, we shall 1) determine the prevalence of the occurrence of clonal B cell expansions in ARC-associated hyperplastic lymphadenopathy, defined the clinical and pathologic features of this pre-lymphomatuos state, and the frequency with which these B cell clones transform to give rise to clinically manifest malignant lymphomas; 2) characterize AIDS-associated B cell derived non-Hodgkin's lymphomas (B-NHL) by combined histopathologic, immunophenotypic, and molecular genetic analysis; 3) determine the prevalence of the occurrence of clonal suppressor/cytotoxic (T3+T4-T8+) T cell subset proliferations in the peripheral blood of patients with AIDS and ARC, the clinical and pathologic features of this pre-leukemic state, and the frequency with which these T cell clones evolve or transform into clinically manifest T cell chronic lymphocytic leukemia; and 4) characterize the natural history of AIDS-associated T cell chronic lymphocytic leukemia with respect to clinical status and course, cytomorphology, cytogenetics, expression and patterns of rearrangement of the T cell receptor genes, functional properties, oncogene expression, and presence of retroviral DNA sequences. The results of these studies should provide considerable new information of both clinical and biological significance concerning the development of lymphoid neoplasia in patients with AIDS, and by inference, in patients with other forms of immune deficiency as well.