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Published online before print December 10, 2007

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(Journal of Leukocyte Biology. 2008;83:718-727.)
© 2008 by Society for Leukocyte Biology

NF-B-dependent control of HIV-1 transcription by the second coding exon of Tat in T cells

Ulrich Mahlknecht^*,1, Isabelle Dichamp^,1, Audrey Varin, Carine Van Lint and Georges Herbein^,2

^* University of Heidelberg, Department of Hematology/Oncology, Heidelberg, Germany;
Department of Virology, IFR 133, EA 3186 Franche-Comté University, Besancon, France; and
Laboratoire de Virologie Moleculaire, Service de Chimie Biologique, Institut de Biologie et de Medecine Moleculaires, Universite Libre de Bruxelles, Gosselies, Belgium

²Correspondence: Department of Virology, Franche-Comté School of Medicine, Hôpital Saint-Jacques, 2 Place Saint-Jacques, F-25030 Besançon Cedex, France. E-mail: gherbein{at}chu-besancon.fr

HIV-1 two-exon transactivator protein (Tat) is a 101-aa protein. We investigated the possible contribution of the extreme C terminus of HIV-1 Tat to maximize nuclear transcription factor NF-B activation, long terminal repeat (LTR) transactivation, and viral replication in T cells. C-terminal deletion and substitution mutants made with the infectious clone HIV-89.6 were assayed for their ability to transactivate NF-B-secreted alkaline phosphatase and HIV-1 LTR-luciferase reporter constructs for low concentrations of Tat. A mutant infectious clone of HIV-89.6 engineered by introducing a stop codon at aa 72 in the Tat open-reading frame (HIVtatexon2) replicated at a significantly lower rate than the wild-type HIV-89.6 in phytohemagglutinin-A/IL-2-stimulated primary peripheral blood lymphocytes. Altogether, our results suggest a critical role for the glutamic acids at positions 92, 94, and 96 or lysines at positions 88, 89, and 90, present in the second encoding Tat exon in activating NF-B, transactivating the HIV-1 LTR and enhancing HIV-1 replication in T cells.

Key Words: LTR stimulation • viral reservoir • AIDS pathogenesis