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Journal of Virology, November 2009, p. 11830-11846, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01466-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Adult AIDS-Like Disease in a Novel Inducible Human Immunodeficiency Virus Type 1 Nef Transgenic Mouse Model: CD4+ T-Cell Activation Is Nef Dependent and Can Occur in the Absence of Lymphophenia{triangledown} ,{dagger}

Mir Munir Ahmed Rahim,1 Pavel Chrobak,1 Chunyan Hu,1 Zaher Hanna,1,2,4 and Paul Jolicoeur1,3,4*

Laboratory of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7,1 Departments of Medicine,2 Microbiology and Immunology, University of Montreal, Montreal, Quebec, Canada H3C 3J7,3 Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3G 1A44

Received 15 July 2009/ Accepted 28 August 2009

CD4C/HIVnef transgenic (Tg) mice express Nef in CD4+ T cells and in the cells of the macrophage/monocyte/dendritic lineage, and they develop an AIDS-like disease similar to human AIDS. In these mice, Nef is constitutively expressed throughout life. To rule out the contribution of any developmental defects caused by early expression of Nef, we generated inducible human immunodeficiency virus type 1 (HIV-1) Nef Tg mice by using the tetracycline-inducible system. Faithful expression of the Nef transgene was induced in (CD4C/rtTA x TRE/HIVNef) or (CD4C/rtTA2S-M2 x TRE/HIVNef) double-Tg mice upon doxycycline (DOX) treatment in drinking water. Long-term treatment of these mice with DOX also led to loss, apoptosis, and activation of CD4+ T cells, this latter phenotype being observed even with low levels of Nef. These phenotypes could be transferred by bone marrow (BM) transplantation, indicating a hematopoietic cell autonomous effect. In addition, in mixed Tg:non-Tg BM chimeras, only Tg and not non-Tg CD4+ T cells exhibited an effector/memory phenotype in the absence of lymphopenia. Finally, the DOX-induced double-Tg mice developed nonlymphoid organ diseases similar to those of CD4C/HIVNef Tg mice and of humans infected with HIV-1. These results show for the first time that adult mice are susceptible to the detrimental action of Nef and that Nef-mediated T-cell activation can be independent of lymphopenia. These Tg mice represent a unique model which is likely to be instrumental for understanding the cellular and molecular pathways of Nef action as well as the main characteristics of immune reconstitution following DOX withdrawal.

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

{triangledown} Published ahead of print on 9 September 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, November 2009, p. 11830-11846, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01466-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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