DEVELOPMENT OF A HUMAN THYMIC ORGAN-CULTURE MODEL FOR THE STUDY OF HIV PATHOGENESIS

The development of effective therapies for the treatment of AIDS would be facilitated by a better understanding of HIV pathogenesis in vivo, While some aspects of pathogenesis may be assessed by standard tissue culture assays, in vivo animal models may provide clues to other aspe cts of HIV-mediated progression toward AIDS, Current animal models inc lude primate models for the study of simian inmunodeficiency virus (SI V) and HIV, SCID-hu and hu-PBL SCID mouse models for the study of HIV, and feline models for the study of feline immunodeficiency virus (FIV ). In general these models are costly and labor intensive, We have dev eloped a simple human fetal thymic organ culture (TOC) system that is permissive for HIV infection and that exhibits pathology similar to th at observed in vivo, A key feature of this system is the time-dependen t destruction of thymocytes typified by the preferential loss of CD4-e xpressing cells, HIV-mediated thymocyte destruction occurs by a proces s involving programmed cell death, We have infected TOC with a panel o f HIV. isolates and found that the resulting viral replicative and pat hogenic profiles are similar to those seen in the SCID-hu Thy/Liv mous e, yet different from profiles observed in standard PHA-blast tissue c ulture assays, In addition, we find that TOC may be used to assess eff icacy of antiviral agents such as AZT (3'-azido-3'-deoxythymidine) and ddI (2',3'-dideoxyinosine) in blocking both viral replication and vir us-induced pathology, These results indicate that this model is amenab le to the systematic manipulation, analysis, and characterization of a variety of HIV virus isolates and antiviral therapies.