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Journal of Virology, March 2008, p. 2813-2820, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02498-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells

Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois 60612,¹ Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195,² Ruth M. Rothstein Core Center, Cook County Bureau of Health Services, Department of Psychiatry,³ Section of Infectious Diseases, Department of Medicine, Rush University Medical Center, Chicago, Illinois 60612⁴

Received 21 November 2007/ Accepted 2 January 2008

The Wnt/β-catenin pathway is involved in cell functions governing development and disease. In modeling postentry restriction of human immunodeficiency virus (HIV) replication in astrocytes, we reported that part of this natural resistance to productive replication of HIV in astrocytes involved expression of proteins of the Wnt/β-catenin signaling pathway. We determined here whether induction of β-catenin signaling in peripheral blood mononuclear cells (PBMCs) can modulate HIV replication. Given that lithium is an inducer of β-catenin signaling, we used it as a tool to determine the impact of β-catenin signaling on HIV replication in PBMCs. We demonstrated that lithium inhibited the replication of T-tropic and primary isolates of HIV by >90% and did so in noncytotoxic/noncytostatic concentrations and in a β-catenin-dependent manner. Specifically, inhibiting β-catenin signaling by transfection of dominant-negative mutant constructs to either T-cell factor 4, the downstream effector of Wnt signaling, or β-catenin, the central mediator of this pathway, abrogated the ability of lithium to inhibit HIV replication. Moreover, when Wnt/β-catenin signaling was inhibited, the level of HIV replication was enhanced by fourfold. To confirm the in vivo relevance of the β-catenin pathway in repressing HIV replication, we evaluated HIV-positive antiretroviral therapy-naive patients who were on lithium therapy. These patients demonstrated a reduction in viral load, which increased as the dose of lithium was reduced. Collectively, these data indicate that β-catenin signaling is an intrinsic molecular pathway restricting HIV replication in PBMCs.

Published ahead of print on 16 January 2008.