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J. Biol. Chem., Vol. 279, Issue 22, 22996-23006, May 28, 2004

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HIV-1 Nef Enhances Both Membrane Expression and Virion Incorporation of Env Products

A MODEL FOR THE NEF-DEPENDENT INCREASE OF HIV-1 INFECTIVITY^*

Ilaria Schiavoni, Susanna Trapp, Anna Claudia Santarcangelo, Valentina Piacentini, Katherina Pugliese, Andreas Baur, and Maurizio Federico¶

From the Laboratory of Virology, Istituto Superiore di Sanità, Rome, 00161 Italy and the Department of Dermatology, University of Erlangen, Erlangen, 91052 Germany

The expression of human immunodeficiency virus Nef increases the viral infectivity through mechanisms still not fully elucidated. Here we report that wild-type (wt) human immunodeficiency virus, type 1 (HIV-1), particles were neutralized by higher concentrations of either anti-Env glycoprotein (gp) 41 antibodies or recombinant soluble human CD4 compared with nef HIV-1. This appeared to be the result of a Nef-induced increase of virion incorporation of both gp41 (transmembrane (TM)) and surface gp120 Env products likely originating from enhanced steady-state levels of cell membrane-associated Env products. This, in turn, seemed to be the consequence of a reduced retention of the Env precursor. Most interesting, we found that both the Nef-directed increase of Env membrane expression and the Nef-induced enhancement of HIV-1 infectivity relied on the presence of the intracytoplasmic domain of TM, supporting the hypothesis of a functional correlation between these effects. Mutagenesis studies allowed us to establish that the two leucine residues at the TM C terminus, which are part of a sorting motif involved in the control of Env membrane expression, and the 181–210-residue Nef C-terminal region were critically involved in the Nef/Env functional interaction. In conclusion, we propose that Nef increases the infectivity of HIV-1 at least in part by enhancing the amounts of Env products incorporated into virus particles.

Received for publication, November 13, 2003 , and in revised form, February 27, 2004.

^* This work was supported by grants from the AIDS project of the Ministry of Health, Rome, Italy. 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.

^¶ To whom correspondence should be addressed: Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. Tel.: 39-6-49903248; Fax: 39-6-49903002; E-mail: federico{at}iss.it.

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