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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2752-2761
IMMUNOBIOLOGY
HIV-1 Nef activates STAT1 in human monocytes/macrophages through
the release of soluble factors
Maurizio Federico,
Zulema Percario,
Eleonora Olivetta,
Gianna Fiorucci,
Claudia Muratori,
Alessandro Micheli,
Giovanna Romeo, and
Elisabetta Affabris
From the Laboratory of Virology, Istituto Superiore di
Sanità, Rome, Italy; Department of Biology, University of Roma
Tre, Rome, Italy; and Institute of Biomedical Technology, CNR, Rome,
Italy.
Monocytes/macrophages play a predominant role in the immunologic
network by secreting and reacting to a wide range of soluble factors.
Human immunodeficiency virus (HIV) infection leads to deep immunologic
dysfunctions, also as a consequence of alterations in the pattern of
cytokine release. Recent studies on in vivo models demonstrated that
the expression of HIV Nef alone mimics many pathogenetic effects of HIV
infection. In particular, Nef expression in monocytes/macrophages has
been correlated with remarkable modifications in the pattern of
secreted soluble factors, suggesting that the interaction of Nef with
monocytes/macrophages plays a role in the pathogenesis of acquired
immunodeficiency syndrome (AIDS). This study sought to define possible
alterations in intracellular signaling induced by Nef in
monocytes/macrophages. Results demonstrate that HIV-1 Nef specifically
activates both  and  isoforms of the signal transducer and
activator of transcription 1 (STAT1). This was observed both by
infecting human monocyte-derived macrophages (MDMs) with HIV-1 deletion
mutants, and by exploiting the ability of MDMs to internalize soluble,
recombinant Nef protein (rNef). STAT1- activation occurs on
phosphorylation of both C-terminal Tyr701 and Ser727 and leads to a
strong binding activity. Nef-dependent STAT1 activation is followed by
increased expression of both STAT1 and interferon regulatory factor-1,
a transcription factor transcriptionally regulated by STAT1 activation.
It was also established that Nef-induced STAT1- / activation
occurs through the secretion of soluble factors. Taken together, the
results indicate that HIV-1 Nef could interfere with STAT1-governed
intracellular signaling in human monocytes/macrophages.
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