HIV-1 Tat protein enhances microtubule polymerization.
BACKGROUND
HIV infection and progression to AIDS is characterized by the depletion of T cells, which could be due, in part, to apoptosis mediated by the extra-cellular HIV-encoded Tat protein as a consequence of Tat binding to tubulin. Microtubules are tubulin polymers that are essential for cell structure and division. Molecules that target microtubules induce apoptosis and are potent anti-cancer drugs. We studied the effect on tubulin polymerization of three Tat variants: Tat HxB2 and Tat Eli from patients who are rapid progressors (RP) and Tat Oyi from highly exposed but persistently seronegative (HEPS) patients. We compared the effect on tubulin polymerization of these Tat variants and peptides corresponding to different parts of the Tat sequence, with paclitaxel, an anti-cancer drug that targets microtubules.


RESULTS
We show that Tat, and specifically, residues 38-72, directly enhance tubulin polymerization. We demonstrate that Tat could also directly trigger the mitochondrial pathway to induce T cell apoptosis, as shown in vitro by the release of cytochrome c from isolated mitochondria.


CONCLUSIONS
These results show that Tat directly acts on microtubule polymerization and provide insights into the mechanism of T cell apoptosis mediated by extra-cellular Tat.
de Mareuil
Jean
J
UMR Univ, Med,/CNRS FRE 2737, Faculté de Pharmacie, Université de la Méditerranée, 27 Bd Jean Moulin, 13385 Marseille, France. jean.boulademareuil@pharmacie.univ-mrs.fr
Carre
Manon
M
Barbier
Pascale
P
Campbell
Grant R
GR
Lancelot
Sophie
S
Opi
Sandrine
S
Esquieu
Didier
D
Watkins
Jennifer D
JD
Prevot
Charles
C
Braguer
Diane
D
Peyrot
Vincent
V
Loret
Erwann P
EP
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D015696:Gene Products, tat / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008870:Microtubules / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism*; D013601:T-Lymphocytes; D014404:Tubulin / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D000972:Antineoplastic Agents, Phytogenic; D015696:Gene Products, tat; D011108:Polymers; D014404:Tubulin; D054322:tat Gene Products, Human Immunodeficiency Virus; D045304:Cytochromes c; D017239:Paclitaxel