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Cytoskeletal Protein Transformation in HIV-1-Infected Macrophage Giant Cells¹

Irena Kadiu^*,, Mary Ricardo-Dukelow^*,, Pawel Ciborowski^*,, and Howard E. Gendelman^2,*,,

^* Laboratory of Neuroregeneration, Department of Pharmacology and Experimental Neuroscience, Department of Biochemistry and Molecular Biology, Department of Internal Medicine, and Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198

The mechanisms linking HIV-1 replication, macrophage biology, and multinucleated giant cell formation are incompletely understood. With the advent of functional proteomics, the characterization, regulation, and transformation of HIV-1-infected macrophage-secreted proteins can be ascertained. To these ends, we performed proteomic analyses of culture fluids derived from HIV-1 infected monocyte-derived macrophages. Robust reorganization, phosphorylation, and exosomal secretion of the cytoskeletal proteins profilin 1 and actin were observed in conjunction with productive viral replication and giant cell formation. Actin and profilin 1 recruitment to the macrophage plasma membrane paralleled virus-induced cytopathicity, podosome formation, and cellular fusion. Poly-L-proline, an inhibitor of profilin 1-mediated actin polymerization, inhibited cytoskeletal transformations and suppressed, in part, progeny virion production. These data support the idea that actin and profilin 1 rearrangement along with exosomal secretion affect viral replication and cytopathicity. Such events favor the virus over the host cell and provide insights into macrophage defense mechanisms used to contain viral growth and how they may be affected during progressive HIV-1 infection.

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 was supported, in part, by National Institutes of Health Grants 2 R37 NS36126, 1 P01 NS31492, 1 P01 NS043985-01, 5 P01 MH64570-03, P20 RR15635 (to H.E.G.), and R21 MH75489 (to P.C.).

² Address correspondence and reprint requests to Dr. Howard E. Gendelman, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center 985880, Nebraska Medical Center, Omaha, NE 68198. E-mail address: hegendel{at}unmc.edu

³ Abbreviations used in this paper: MP, mononuclear phagocyte; GCI, Giant Cell Index; LC-MS/MS, liquid chromatography mass spectrometry; MDM, monocyte-derived macrophage; MGC, multinucleated giant cell; MOI, multiplicity of infection; P-L-P, poly-L-proline; RT, reverse transcriptase; SELDI-TOF, surface-enhanced laser desorption ionization time-of-flight; WCX2, weak cation exchange.