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CCR5 signaling through phospholipase D involves p44/42 MAP-kinases and promotes HIV-1 LTR-directed gene expression

Sylvain Paruch^*,, Mylène Heinis^*,, Julie Lemay^*,, Guillaume Hoeffel^*,, Concepción Marañón^*,, Anne Hosmalin^*, and Axel Périanin^*,,1

^* Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.

Inserm, U567, Paris, France.

¹Correspondence: Institut Cochin, Département de Biologie Cellulaire, Pavillon G. Roussy 5^ème Etage, P502, 27, rue du Faubourg St. Jacques, 75014, Paris, France. E-mail: perianin{at}cochin.inserm.fr

The chemokine receptor CCR5 plays an important role as an entry gate for the human immunodeficiency virus-1 (HIV-1) and for viral postentry events. Among signal transducers used by chemoattractant receptors, the phosphatidylcholine-specific phospholipase D (PLD) produces large amounts of second messengers in most cell types. However, the relevance of PLD isoforms to CCR5 signaling and HIV-1 infection process remains unexplored. We show here that CCR5 activation by MIP-1β in HeLa-MAGI cells triggered a rapid and substantial PLD activity, as assessed by mass choline production. This activity required the activation of ERK1/2-MAP kinases and involved both PLD1 and PLD2. MIP-1β also promoted the activation of an HIV-1 long terminal repeat (LTR) by the transactivator Tat in HeLa P4.2 cells through a process involving ERK1/2. Expression of wild-type and catalytically inactive PLDs dramatically boosted and inhibited the LTR activation,respectively, without altering Tat expression. Wild-type and inactive PLDs also respectively potentiated and inhibited HIV-1_BAL replication in MAGI cells. Finally, in monocytic THP-1 cells, antisense oligonucleotides to both PLDs dramatically inhibited the HIV-1 replication. Thus, PLD is activated downstream of ERK1/2 upon CCR5 activation and plays a major role in promoting HIV-1 LTR transactivation and virus replication, which may open novel perspectives to anti-HIV-1 strategies.—Paruch, S., Heinis, M., Lemay, J., Hoeffel, G., Marañón, C., Hosmalin, A., Périanin, A. CCR5 signaling through phospholipase D involves p44/42 MAP-kinases and promotes HIV-1 LTR-directed gene expression.

Key Words: HIV-1 coreceptors • signal transducers • infection