AEGiS-14IAC: Systemic delivery of TAT and the effects on the host and HIV replication.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

Systemic delivery of TAT and the effects on the host and HIV replication.

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. A10052)

Lin XL, Kanazawa SK, Irwin DI, Peterlin BM
University of California, San Francisco, San Francisco, CA 94143, United States

BACKGROUND: The viral persistence in optimally treated HIV patients poses a major therapeutic problem. This state of viral latency is characterized by the lack of Tat phenotype, i.e. only promoter proximal transcription without evidence of transcriptional elongation is observed, which is the hallmark of Tat. Exogenous Tat can activate viral replication in these cells and/ or administer different lymphokines or cytokines systemically to activate viral replication. However, systematic T cell activation can lead to toxic shock. Tat however seems to be rather harmless by itself. We therefore propose to determine if systemic administration of Tat has deleterious side effects on the organism.

METHODS: We have developed a Tat transgenic model, that a secretion leader peptide sequence is 5' upstream and in frame with the Tat sequence, the C-terminus of Tat is linked to GFP. This hybrid protein is driven by the RIP7 promoter and targeted to the pancreatic beta cells. In this model Tat is secreted and circulating in the blood.

RESULTS: We have detected high level of Tat protein in the serum and the islet and also the GFP fluorescent of the Tat-GFP fusion protein could be detected in all organs of the transgenic animals examined. No obvious side effects have been observed in those mice. The CD4+ between CD8+ T cells in theses animals are normal compared to the wild-type littermates. No significant T cell apoptosis was observed in the transgenic animals. The secreted Tat protein is biologically active, it is able to activate HIV-1 LTR. When equal amount of Tat protein was added to the latent U1 cell line, it is able to induce virus production of this otherwise latent cell line.

CONCLUSIONS: This study has provided valuable argument about the roles of Tat in T cell activation apoptosis and CNS disfunction. These finding could lead to the use of Tat protein as an adjunct therapy in the treatment of AIDS.

Keywords: AEGIS, Gene Products, tat, Virus Replication, HIV Infections, HIV Long Terminal Repeat, Virus Latency, Transcription, Genetic, HIV Seropositivity, Promoter Regions (Genetics), T-Lymphocytes, Luminescent Proteins, green fluorescent protein, Animal, Mice, Human, virology, genetics

020707
A10052