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The Src Kinase Lck Facilitates Assembly of HIV-1 at the Plasma Membrane¹

Amy B. Strasner^*, Malini Natarajan^*, Tom Doman, Douglas Key, Avery August^*,, and Andrew J. Henderson^2,

^* Intergrated Bioscience Program in Immunobiology, Huck Institute of the Life Sciences, Department of Veterinary and Biomedical Sciences, and Center of Molecular Immunology and Infectious Diseases, The Pennsylvania State University, University Park, PA 16802; and Department of Medicine, Section of Infectious Diseases, Center for HIV/AIDS Care and Research, Boston University School of Medicine, Boston, MA 02118

HIV type 1 (HIV-1) assembly and egress are driven by the viral protein Gag and occur at the plasma membrane in T cells. Recent evidence indicates that secretory vesicles and machinery are essential components of virus packaging in both T cells and macrophages. However, the pathways and cellular mediators of Gag targeting to the plasma membrane are not well characterized. Lck, a lymphoid specific Src kinase critical for T cell activation, is found in the plasma membrane as well as various intracellular compartments and it has been suggested to influence HIV-1 replication. To investigate Lck as a potential regulator of Gag targeting, we assessed HIV-1 replication and Gag-induced virus-like particle release in the presence and absence of Lck. Release of HIV-1 and virus-like particles was reduced in the absence of Lck. This decrease in replication was not due to altered HIV-1 infection, transcription or protein translation. However, in T cells lacking Lck, HIV-1 accumulated intracellularly. In addition, expressing Lck in HeLa cells promoted HIV-1 Gag plasma membrane localization. Palmitoylation of the Lck unique domain, which is essential for directing Lck to the plasma membrane, was critical for its effect on HIV-1 replication. Furthermore, HIV-1 Gag directly interacted with the Lck unique domain in the context of infected cells. These results indicate that Lck plays a key role in targeting HIV-1 Gag to the plasma membrane in T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by Penn State Tobacco Formula Funds and by Grants AI46261 and AI62467 from the National Institutes of Health (to A.J.H.).

² Address correspondence and reprint requests to Dr. Andrew J. Henderson, Department of Medicine, Section of Infectious Diseases, Center for HIV/AIDS Care and Research, Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118-2393. E-mail address: andrew.henderson{at}bmc.org

³ Abbreviations used in this paper: HIV-1, HIV type 1; VLP, virus-like particle; VSV-G, vesicular stomatitis virus glycoprotein; PLAP, placental alkaline phosphatase; UD, unique domain; SH, Src homology.