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Journal of Virology, May 2006, p. 4469-4481, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4469-4481.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Importance of the N-Distal AP-2 Binding Element in Nef for Simian Immunodeficiency Virus Replication and Pathogenicity in Rhesus Macaques

Matthias Brenner,1,{dagger} Jan Münch,1,{dagger} Michael Schindler,1 Steffen Wildum,1 Nicole Stolte,2 Christiane Stahl-Hennig,2 Dietmar Fuchs,2 Kerstin Mätz-Rensing,2 Monika Franz,2 Jonathan Heeney,3 Peter Ten Haaft,3 Tomek Swigut,4 Katarzyna Hrecka,4 Jacek Skowronski,4 and Frank Kirchhoff1*

Department of Virology, Universitätsklinikum, Albert-Einstein-Allee 11 89081 Ulm, Germany,1 German Primate Center, Kellnerweg 4, 37077 Goettingen, Germany,2 Biomedical Primate Research Centre, 2280GH Rijswijk, The Netherlands,3 Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 117244

Received 5 October 2005/ Accepted 6 February 2006

Point mutations in SIVmac239 Nef disrupting CD4 downmodulation and enhancement of virion infectivity attenuate viral replication in acutely infected rhesus macaques, but changes selected later in infection fully restore Nef function (A. J. Iafrate et al., J. Virol. 74:9836-9844, 2000). To further evaluate the relevance of these Nef functions for viral persistence and disease progression, we analyzed an SIVmac239 Nef mutant containing a deletion of amino acids Q64 to N67 ({Delta}64-67Nef). This mutation inactivates the N-distal AP-2 clathrin adaptor binding element and disrupts the abilities of Nef to downregulate CD4, CD28 and CXCR4 and to stimulate viral replication in vitro. However, it does not impair the downmodulation of CD3 and class I major histocompatibility complex (MHC-I) or MHC-II and the upregulation of the MHC-II-associated invariant chain, and it has only a moderate effect on the enhancement of virion infectivity. Replication of the {Delta}64-67Nef variant in acutely infected macaques was intermediate between grossly nef-deleted and wild-type SIVmac239. Subsequently, three of six macaques developed moderate to high viral loads and developed disease, whereas the remaining animals efficiently controlled SIV replication and showed a more attenuated clinical course of infection. Sequence analysis revealed that the deletion in nef was not repaired in any of these animals. However, some changes that slightly enhanced the ability of Nef to downmodulate CD4 and moderately increased Nef-mediated enhancement of viral replication and infectivity in vitro were observed in macaques developing high viral loads. Our results imply that both the Nef functions that were disrupted by the {Delta}64-67 mutation and the activities that remained intact contribute to viral pathogenicity.

* Corresponding author. Mailing address: Department of Virology, Universitätsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49-731-50023344. Fax: 49-731-50023337. E-mail: frank.kirchhoff{at}medizin.uni-ulm.de.

{dagger} M.B. and J.M. contributed equally to this study.

Journal of Virology, May 2006, p. 4469-4481, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4469-4481.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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