Role of the accessory Vpr and Vpu proteins and upstream LTR U3 sequences in HIV-1 replication and cytopathicity in human lymphoid tissue ex vivo

Understanding the pathogenesis of AIDS requires adequate experimental models. In HIV-1 infected individuals the bulk of viral replication and the critical events in AIDS progression occur in lymphoid tissues. These processes can be studied in ex vivo-infected HLT represent-ing a typical adult lymphoid tissue (tonsils). This system supports productive HIV-1 infection without exogenous stimulation and provides a useful model for studying the importance of different proteins for HIV-1 replication and CD4+ T cell depletion in infected individuals. In the present study, the HLT system was used as a model to assess the potential role of the ac-cessory HIV-1 Vpr and Vpu proteins and the LTR U3 region for viral replication and patho-genicity in HIV-1 infected individuals. Thus, the specific goals of the present doctoral thesis were (1) to assess the relevance of three arginine residues in the C-terminal mitochondriotoxic domain of Vpr for its apoptogenic activity and hence in the clinical course of HIV-1 infection; (2) to elucidate whether Vpu-mediated CD4 down-modulation is sufficient for effective viral spread and cytopathicity in ex vivo-infected HLT; and (3) to clarify whether upstream U3 se-quences in the HIV-1 LTR are required for efficient viral replication and CD4+ T cell deple-tion in lymphoid tissues. The results of this doctoral thesis suggest that (1) point mutations in Vpr may affect the clinical course of infection; (2) Vpu-mediated CD4 down-modulation is most likely not critical for AIDS pathogenesis; and (3) the U3 region has probably limited significance in the pathogenesis of AIDS. Thus, the results of this doctoral thesis provide novel insights into the possible role of the HIV-1 Vpr and Vpu proteins and the LTR U3 re-gion in the pathogenesis of AIDS