The HIV-1 Nef Protein Interferes with Phosphatidylinositol 3-Kinase Activation 1

doi:10.1074/jbc.271.12.6590

The HIV-1 Nef Protein Interferes with Phosphatidylinositol 3-Kinase Activation 1 (*)

From the Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, 10126 Torino, Italy

^¶ To whom correspondence should be addressed:
Institute for Cancer Research (IRCC), corso Massimo d'Azeglio 52, 10126 Torino, Italy
. Tel.: 39-11-670-7739; Fax: 39-11-650-9105.

Abstract

nef is a human immunodeficiency virus (HIV) gene encoding a 27-kDa myristoylated protein with structural features of a signal transducing molecule, but whose functions are largely unknown. We studied the interactions of Nef with the signal transduction pathways triggered by the platelet-derived growth factor (PDGF) receptor. The association of phosphatidylinositol (PI) 3-kinase with the activated receptor was severely impaired by nef expression. Conversely, PDGF-induced receptor tyrosine phosphorylation, binding to phospholipase C- and to Ras-GAP were not modified. Microtubule-associated protein kinase activation and intracellular calcium influx in response to PDGF were either unaffected or only slightly enhanced. Nef significantly reduced the proliferative response to the growth factor, while the chemotactic response was unchanged. These data show that Nef affects selectively the PI 3-kinase signaling pathway and suggest that this interference results in some of the HIV adverse effects on host cell functions.

Footnotes

↵^§ Recipient of an AIDS-Fellowship from the Istituto Superiore di Sanitá.
↵* This work was supported in part by the VII AIDS Research Project, Italian Ministry of Health Grant 920435. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

HIV-1

human immunodeficiency virus 1

PI 3-kinase

phosphatidylinositol 3-kinase

PDGF

platelet-derived growth factor

PLC-

phospholipase C-

Ras-GAP

Ras GTPase activating protein

MAP

microtubule-associated protein

SIV

simian immunodeficiency virus

PBL

peripheral blood cells

TCR

T cell receptor

PIP

phosphatidylinositol bisphosphate

SH2

Src homology region 2

SH3

Src homology region 3

IL-2

interleukin 2

DMEM

Dulbecco's modified Eagle's medium

FCS

fetal calf serum.
- Received September 18, 1995.
- Revision received January 12, 1996.