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Journal of Virology, May 2007, p. 4677-4693, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02691-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Primary Human Immunodeficiency Virus Type 1 Nef Alleles Show Major Differences in Pathogenicity in Transgenic Mice{triangledown}

Elena Priceputu,1,{dagger} Zaher Hanna,1,2,4,{dagger}* Chunyan Hu,1 Marie-Chantal Simard,1 Patrick Vincent,1 Steffen Wildum,5 Michael Schindler,5 Frank Kirchhoff,5 and Paul Jolicoeur1,3,4*

Laboratory of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada,1 Departments of Medicine,2 Microbiology and Immunology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada,3 Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada,4 Institute of Virology, University of Ulm, Ulm, Germany5

Received 6 December 2006/ Accepted 14 February 2007

We previously reported that the human immunodeficiency virus type 1 NL4-3 Nef is necessary and sufficient to induce a severe AIDS-like disease in transgenic (Tg) mice when the protein is expressed under the regulatory sequences of the human CD4 gene. We have now assayed additional Nef alleles (SF2, JR-CSF, YU10x, and NL4-3 [T71R] Nef alleles), including some from long-term nonprogressors (AD-93, 032an, and 039nm alleles) in the same Tg system and compared their pathogenicities. All these Nef alleles downregulated cell surface CD4 in human cells in vitro and also, with the exception of NefYU10x, in Tg CD4+ T cells. Depletion of double-positive and single-positive thymocytes occurred with all alleles but was less pronounced in NefYU10x Tg mice. A loss of peripheral CD4+ T cells was observed with all alleles but was minimal in NefYU10x Tg mice. In Nef032an and NefSF2 Tg mice, T-cell loss was severe despite lower levels of Tg expression, suggesting a higher virulence of these alleles. All Nef alleles except the NefYU10x and NefNL4-3(T71R) alleles induced an enhanced activated memory (CD25+ CD69+ CD44high CD45RBlow CD62Llow) and apoptotic phenotype. Also, all could interact with and/or activate PAK2 except the NefJR-CSF allele. Organ (lung and kidney) diseases were present in NefNL4-3(T71R), Nef032an, Nef039nm, and NefSF2 Tg mice, despite very low levels of Tg expression for the last strain. However, no organ disease or minimal organ disease developed in NefYU10x and NefAD-93 Tg mice and NefJR-CSF Tg mice, respectively, despite high levels of Tg expression. Our data show that important differences in the pathogenicities of various Nef alleles can be scored in Tg mice. Interestingly, our results also revealed that some phenotypes can segregate independently, such as CD4+ T-cell depletion and activation, as well as severe depletion of thymic CD4+ T cells and peripheral CD4+ T cells. Therefore, expression of Nef alleles in Tg mice under the CD4C regulatory elements represents a novel assay for measuring their pathogenicity. Because of the very high similarity of this murine AIDS-like disease to human AIDS, this assay may have a predictive value regarding the behavior of Nef in infected humans.

* Corresponding author. Mailing address: Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada. Phone for Paul Jolicoeur: (514) 987-5569. Fax: (514) 987-5794. E-mail: paul.jolicoeur{at}ircm.qc.ca. Phone for Zaher Hanna: (514) 987-5571. Fax: (514) 987-5604. E-mail: Zaher.Hanna{at}ircm.qc.ca

{triangledown} Published ahead of print on 21 February 2007.

{dagger} These two authors contributed equally to this work.

Journal of Virology, May 2007, p. 4677-4693, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02691-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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