Proliferative activity of extracellular HIV-1 Tat protein in human epithelial cells: expression profile of pathogenetically relevant genes.
BACKGROUND
Tat 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.


RESULTS
small 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.


CONCLUSIONS
extracellular 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.
Bettaccini
Alessia A
AA
Dipartimento di Scienze Cliniche e Biologiche, Università dell' Insubria, Varese, Italy. mabodio@tin.it
Baj
Andreina
A
Accolla
Roberto S
RS
Basolo
Fulvio
F
Toniolo
Antonio Q
AQ
D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004260:DNA Repair; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D015696:Gene Products, tat / Q000009:adverse effects / Q000494:pharmacology*; D015658:HIV Infections / Q000473:pathology*; D006801:Humans; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D016213:Cyclins; D015696:Gene Products, tat; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D018844:Cyclin-Dependent Kinases