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B Signaling, Elastase Localization, and Phagocytosis Differ in HIV-1 Permissive and Nonpermissive U937 Clones1
* Institute for Human Genetics and Biochemistry and
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10003;
Department of Biology, San Diego State University, San Diego, CA 92182;
Dental Research Center, University of North Carolina, Chapel Hill, NC 27599; and
¶ Antara BioSciences, Mountain View, CA 94043
To identify positive or negative factors for HIV-1 infectivity, clones from the U937 promonocytic cell line that express similar levels of CD4 and CXCR4, but differ in HIV-1 susceptibility, were compared. In contrast to HIV-1 permissive clone 10 (plus), nonpermissive clone 17 (minus) was adherent to coverslips coated with chemokines, was phagocytic, killed bacteria, and expressed human leukocyte elastase (HLE) in a granule-like compartment (HLEG) that was never detected at the cell surface (HLECS). In contrast to the minus clone, the plus clone expressed HLE on the cell surface and was adherent to coverslips coated with the HLECS ligands 
1proteinase inhibitor (1PI, 1antitrypsin) and the HIV-1 fusion peptide. The phosphorylation status of several important signaling proteins was studied at the single cell level. Tumor suppressor p53, NF-
B p65, and Akt were constitutively phosphorylated in the plus clone, but not in the minus clone. Surprisingly, both 1PI and LPS induced phosphorylation of NF-B p65 Ser-536 in both clones, but induced dephosphorylation of Ser-529 in the plus clone only. HIV-1 permissivity was conferred to the minus clone in a manner that required stimulation by both 1PI and LPS and was coincident to NF-B p65 phosphorylation/dephosphorylation events as well as translocation of HLE to the cell surface. Even when stimulated, the minus clone exhibited greater reverse transcriptase activity, but less p24, than the plus clone. Results presented suggest that HIV-1 uptake and production efficiency are influenced by signaling profiles, receptor distribution, and the phagocytic capacity specific to the stage of differentiation of the CD4+ target cell.
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 by the University of North Carolina Center for AIDS Research and Harry Winston Research Foundation.
2 Address correspondence and reprint requests to Dr. C. L. Bristow, Director of Research, Institute for Human Genetics and Biochemistry, Department of Medicine, Mount Sinai School of Medicine, 227 East 19th Street, Room D477, New York, NY 10003. E-mail address: Cynthia.Bristow{at}mssm.edu
3 Abbreviations used in this paper: HLE, human leukocyte elastase; HLEG, granule-associated HLE; HLECS, cell-surface HLE; TEM, transmission electron microscopy; DAPI, 4'-6-diamidino-2-phenylindole; PI, propidium iodide; 1ACT 1, antichymotrypsin; ATIII, antithrombin III; MAAPVCK, methoxysuccinyl-L-Ala-L-Ala-L-Pro-L-Val-chloromethylketone; TPCK, N-tosyl-L-phenylalanine chloromethylketone; INR, internally normalized ratio; LRP, lipoprotein receptor-related protein; CatG, cathepsin G.
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