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Blood, 15 October 2003, Vol. 102, No. 8, pp. 2925-2932.
Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-03-0833.
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IMMUNOBIOLOGY
Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development
Veronique Stove,
Evelien Naessens,
Christophe Stove,
Tomek Swigut,
Jean Plum, and
Bruno Verhasselt
From the Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent University Hospital, Ghent, Belgium; the Department of Radiotherapy and Nuclear Medicine, Ghent University, Ghent University Hospital, Ghent, Belgium; and Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
The HIV-1 gene nef is important for progression toward AIDS and cellular depletion of the infected thymus. Expression of the Nef protein alone impairs human thymopoiesis. Here, we performed a structure-function analysis of the Nef protein by comparing the effect on T-cell development of different nef alleles, either wild type or defective for selected functions, expressed by human thymocytes. We show that Nef-mediated impaired thymopoiesis is not due to altered surface marker trafficking, nor dependent on oligomerization of Nef. By contrast, mutations in the myristoylation site and in signaling sites of Nef, ie, sites important for interaction with phosphofurin acidic cluster sorting protein-1 (PACS-1), Src homology domain 3 (SH3) domains, and p21-activated kinase 2 (PAK2), were found to be critical for its effect on T-cell development. These results point to sites in Nef to target therapeutically for restoration of thymopoiesis in HIV infection.
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