Abstract
BackgroundTat is being tested as a component of HIV vaccines. Tat activity has been mainly investigated on cells of lymphoid/hematopoietic lineages. HIV-1, however, is known to infect many different cells of both solid organs and mucosal surfaces. The activity of two-exon (aa 1–101) and synthetic (aa 1–86) Tat was studied on mammary and amniotic epithelial cells cultured under low serum conditions.Resultssmall concentrations of Tat (100 ng/ml) stimulated cell proliferation. Tat antibodies neutralized the mitogenic Tat activity. Changes of gene expression in Tat-treated cells were evaluated by RT-PCR and gene-array methods. Within 4 hours of treatment, exposure to Tat is followed by up-regulation of some cell cycle-associated genes (transcription factors, cyclin/cdk complexes, genes of apoptotic pathways) and of genes relevant to HIV pathogenesis [chemokine receptors (CXCR4, CCR3), chemotactic cytokines (SDF-1, RANTES, SCYC1, SCYE1), IL6 family cytokines, inflammatory cytokines, factors of the TGF-beta family (TGFb, BMP-1, BMP-2)]. Up-regulation of anti-inflammatory cytokines (IL-10, IL-19, IL-20), a hallmark of other persistent viral infections, was a remarkable feature of Tat-treated epithelial cell lines.Conclusionextracellular Tat is mitogenic for mammary and amniotic epithelial cells and stimulates the expression of genes of pathogenetic interest in HIV infection. These effects may favor virus replication and may facilitate the mother-to-child transmission of virus.
Highlights
transactivator protein (Tat) is being tested as a component of HIV vaccines
Numerous extracellular roles for the HIV-1 transactivator protein (Tat) have emerged from experiments showing that Tat is taken up by cultured cells, enters the nucleus, and transactivates genes linked to the HIV LTR [1]
Cell proliferation in response to exogenous Tat Preliminary experiments with a variety of epithelial cell lines have shown that only marginal proliferative responses to Tat were observed when cells were grown in complete medium
Summary
Tat is being tested as a component of HIV vaccines. Tat activity has been mainly investigated on cells of lymphoid/hematopoietic lineages. Experiments showing that recombinant Tat was able to inhibit antigen-induced, but not mitogen-induced, proliferation of peripheral blood mononuclear cells indicated Tat as a viral immunosuppressant [2]. This view has been confirmed by subsequent observations indicating that: a) Tat down-regulates HLA class I [3] and class II [4] expression in T-lymphocytes and macrophages, b) Tat (page number not for citation purposes). Tat has been shown to act through several pathways to establish an adequate cellular environment enhancing viral replication
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