title: Molecular mechanisms involved in HIV-1-Tat mediated inhibition of telomerase activity in human CD4(+) T lymphocytes.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection is characterized by a progressive decline of CD4(+) T cells and by other immune disorders that are similar to those observed during aging and which lead eventually to AIDS. One of the mechanisms involved in HIV-1 induced immunodeficiency may be the lack of telomerase induction and the consequent impairment of the potential required for CD4(+) T cell expansion. Telomerase compensates for the progressive telomere loss during cell division and preserves the replicative potential of T lymphocytes after repeated antigenic stimulation. The enzyme is activated by post-translational modifications, such as phosphorylation and also by the nuclear import of its catalytic subunit hTERT from the cytoplasm. In previous studies we found a reduction of telomerase activity in the nucleus of CD4(+) T cells infected with HIV-1 or non-infected but exposed to Tat protein. However, the mechanism for this loss of activity has not been elucidated yet. In the present study, we found that HIV-1 Tat inhibited telomerase activity in CD4(+) T cells by different mechanisms. First, it reduced nuclear levels of hTERT. Secondly, this protein perturbed the AKT pathway and the molecular interaction with the chaperones required for hTERT phosphorylation, nuclear import and activation. These results suggest that in addition to inducing direct cell death, HIV infection may also reduce the replicative potential of non-infected CD4(+) T cells and this may contribute to the overall immunodeficiency in AIDS patients.
authors.affiliation: Department of System Medicine, Pharmacology Section, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Comandini
authors.forename: Chiara
authors.initials: C
authors.lastname: Naro
authors.forename: Riccardo
authors.initials: R
authors.lastname: Adamo
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
authors.forename: Alessio
authors.initials: A
authors.lastname: Lanna
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonmassar
authors.forename: Ornella
authors.initials: O
authors.lastname: Franzese
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018841:HSP90 Heat-Shock Proteins; D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase