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Nef-Mediated Enhancement of Virion Infectivity and Stimulation of Viral Replication Are Fundamental Properties of Primate Lentiviruses

Jan Münch,^1, Devi Rajan,^1, Michael Schindler,^1,, Anke Specht,^1, Elke Rücker,¹ Francis J. Novembre,² Eric Nerrienet,^3, Michaela C. Müller-Trutwin,⁴ Martine Peeters,⁵ Beatrice H. Hahn,⁶ and Frank Kirchhoff^1*

Institute of Virology, University of Ulm, 89081 Ulm, Germany,¹ Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30329,² Centre Pasteur du Cameroun, BP1274, Yaounde, Cameroon,³ Unité de Biologie des Rétrovirus, Institut Pasteur, 75015 Paris, France,⁴ Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294,⁵ Laboratoire Retrovirus, UMR145, Institut de Recherche pour le Development and Department of International Health, University of Montpellier, 34032 Montpellier, France⁶

Received 27 April 2007/ Accepted 26 September 2007

Nef is a multifunctional accessory protein of primate lentiviruses. Recently, it has been shown that the ability of Nef to downmodulate CD4, CD28, and class I major histocompatibility complex is highly conserved between most or all primate lentiviruses, whereas Nef-mediated downregulation of T-cell receptor-CD3 was lost in the lineage that gave rise to human immunodeficiency virus type 1 (HIV-1). Whether or not other Nef activities are preserved between different groups of primate lentiviruses remained to be determined. Here, we show that nef genes from a large variety of HIVs and simian immunodeficiency viruses (SIVs) enhance virion infectivity and stimulate viral replication in human cells and/or in ex vivo infected human lymphoid tissue (HLT). Notably, nef alleles from unpassaged SIVcpz and SIVsmm enhanced viral infectivity, replication, and cytopathicity in cell culture and in ex vivo infected HLT as efficiently as those from HIV-1 and HIV-2, their human counterparts. Furthermore, nef genes from several highly divergent SIVs that have not been found in humans were also highly active in human cells and/or tissues. Thus, most primate lentiviral Nefs enhance virion infectivity and stimulate viral replication. Moreover, our data show that SIVcpz and SIVsmm Nefs do not require adaptive changes to perform these functions in human cells or tissues and support the idea that nef alleles from other primate lentiviruses would also be capable of promoting efficient virus spread in humans.

Published ahead of print on 10 October 2007.

J.M., D.R., M.S., and A.S. contributed equally to this work.

Present address: Heinrich Pette Institut, 20251 Hamburg, Germany.

Present address: HIV/Hepatitis Laboratory, Institut Pasteur du Cambodge, BP983, Phnom Penh, Cambodia.