CELL INTERACTIONS IN THREE DIMENSIONAL TISSUE CULTURE

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Complex cell-cell interactions in tissues are the basis for their normal and pathological behavior. HIV infection of lymphoid tissue leads to deterioration of these interactions and to development of immunodeficiency. The latter is often is preceded by the shift of HIV phenotype from macrophage (M)-tropic (dominant early in the course of infection) to T cell (T)-tropic. Neither the mechanisms of immunodeficiency, nor its causative relation to the emergence of T-tropic virus is fully understood. To elucidate the immunopathogenetic mechanisms of HIV infection in the context of human tissue under controlled conditions in vitro, we are using our system of histocultured blocks of human tonsils. When challenged in vitro with recall antigens, blocks of cultured tissue respond by production of specific antibodies. In vitro infection of human lymphoid tissue with laboratory strains and primary isolates of HIV-1 dysregulates this immune response in an isolate-dependent manner: T-tropic HIV-1 variants dramatically suppress the tissue immune response, while M-tropic HIV variants enhance the immune response to recall antigen. The developed humoral immunodeficiency is caused by the defects in B cells rather than by the deficiency in extracellular factors. The impairment of B cells takes place in the context of HIV-infected lymphoid tissue, probably due to the defective cell-cell contacts, or short-range soluble factors confined to the tissues. Replication of M-tropic, but not of T-tropic HIV-1 in lymphoid tissue was inhibited by exogenous CC chemokines MIP-1a or MIP-1b. Infection of lymphoid tissue in vitro with T-tropic, but not with M-tropic HIV-1 isolate upregulated endogenous MIP-1a and MIP-1b. Thus, viral tropism is the determinant of humoral immunodeficiency in HIV-infected tissues in vitro. Since both the upregulated CC chemokines are inhibitory for M-tropic but indifferent for T-tropic HIV variants, the induction of MIP-1a and MIP-1b may contribute to the shift of viral tropism from M to T in HIV-infected patients. The system of cultured blocks of intact human lymphoid tissue may be useful for guiding the development of combinations of CC chemokines or CC chemokine-based drugs with other antivirals for clinical application.