[70] DUAL ROLE OF PROSTATIN IN INHIBITION OF INFECTION AND REACTIVATION OF LATENCY OF HUMAN IMMUNODEFICIENCY VIRUS IN PRIMARY BLOOD LYMPHOCYTES AND IN LYMPHOID TISSUE

2nd International AIDS Society Conference on HIV Pathogenesis and Treatment

Paris, France - July 13 - 16, 2003

[TITLE:] DUAL ROLE OF PROSTATIN IN INHIBITION OF INFECTION AND REACTIVATION OF LATENCY OF HUMAN IMMUNODEFICIENCY VIRUS IN PRIMARY BLOOD LYMPHOCYTES AND IN LYMPHOID TISSUE

[AUTHOR(S):] A Biancotto¹, JC Grivel², M Pion¹, F Gondois-Rey¹, R Vigne¹, S Brown³, LB Margolis² and I Hirsch¹
¹ INSERM U372; ² Unité de Pathogénie des Infections à Lentivirus; and ³ Parc Scientifique et Technologique de Luminy, Marseille, France

IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 70
Antiviral Therapy 2003; 8(Suppl. 1):S202

[ABSTRACT:] Objective: To design strategies for purging latent reservoirs of human immunodeficiency virus type 1 (HIV-1), we investigated mechanisms by which a non-tumour-promoting phorbol ester, prostratin, inhibits infection of CD4 T lymphocytes and in parallel reactivates viral latency.

Design and Methods: CD4 T lymphocytes from primary blood mononuclear cells (PBMC) or in lymphoid tissue stimulated with prostratin were infected with HIV-1 to investigate the effects of prostratin on cellular susceptibility to the virus. Capacity of prostratin to reactivate HIV latency was tested in CD4 T cells harbouring pre-integrated and integrated latent proviruses.

Results: Our results show that prostratin stimulated CD4 T cells in PBMC and lymphoid tissue in an aberrant way. It induced expression of activation markers CD25 and CD69 but inhibited cell cycling. HIV-1 uptake was reduced in prostratin-stimulated CD4 T cells consistently with down-modulation of CD4 and CXCR4 receptors in PBMC and lymphoid tissue. At postentry level, prostratin reduced completion of reverse transcription of the viral genome in lymphatic tissue. Prostratin reactivated HIV-1 from pre- and post-integration latency in resting CD4+ T cells in PBMC and lymphatic tissue.

Conclusions: While prostratin stimulation restricts susceptibility of primary resting CD4 T cells to HIV at the virus cellentry and the reverse transcription levels, it efficiently reactivates expression of pre-integrated and integrated latent HIV-1. This dual role makes of prostratin an excellent candidate for the elimination of persistent HIV infection from latent reservoirs in HAART-treated patients.

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