HIV-1 Nef enhances both membrane expression and virion incorporation of Env products. A model for the Nef-dependent increase of HIV-1 infectivity

• Published in: The Journal of biological chemistry Vol. 279; no. 22; pp. 22996 - 23006
• Main Authors: Schiavoni, Ilaria, Trapp, Susanna, Santarcangelo, Anna Claudia, Piacentini, Valentina, Pugliese, Katherina, Baur, Andreas, Federico, Maurizio
• Format: Journal Article
• Language: English
• Published: United States 28.05.2004
• Subjects: Gene Expression Regulation, Viral; Gene Products, nef - genetics; Gene Products, nef - metabolism; HIV Envelope Protein gp41 - genetics; HIV Envelope Protein gp41 - metabolism; HIV-1 - pathogenicity; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; nef Gene Products, Human Immunodeficiency Virus; Virulence - genetics; Virus Replication
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M312453200

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 Deltanef 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.