Selective expression of human immunodeficiency virus Nef in specific immune cell populations of transgenic mice is associated with distinct AIDS-like phenotypes.
We previously reported that CD4C/human immunodeficiency virus (HIV)(Nef) transgenic (Tg) mice, expressing Nef in CD4(+) T cells and cells of the macrophage/dendritic cell (DC) lineage, develop a severe AIDS-like disease, characterized by depletion of CD4(+) T cells, as well as lung, heart, and kidney diseases. In order to determine the contribution of distinct populations of hematopoietic cells to the development of this AIDS-like disease, five additional Tg strains expressing Nef through restricted cell-specific regulatory elements were generated. These Tg strains express Nef in CD4(+) T cells, DCs, and macrophages (CD4E/HIV(Nef)); in CD4(+) T cells and DCs (mCD4/HIV(Nef) and CD4F/HIV(Nef)); in macrophages and DCs (CD68/HIV(Nef)); or mainly in DCs (CD11c/HIV(Nef)). None of these Tg strains developed significant lung and kidney diseases, suggesting the existence of as-yet-unidentified Nef-expressing cell subset(s) that are responsible for inducing organ disease in CD4C/HIV(Nef) Tg mice. Mice from all five strains developed persistent oral carriage of Candida albicans, suggesting an impaired immune function. Only strains expressing Nef in CD4(+) T cells showed CD4(+) T-cell depletion, activation, and apoptosis. These results demonstrate that expression of Nef in CD4(+) T cells is the primary determinant of their depletion. Therefore, the pattern of Nef expression in specific cell population(s) largely determines the nature of the resulting pathological changes.
Hanna
Zaher
Z
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada. hannaz@ircm.qc.ca
Priceputu
Elena
E
Chrobak
Pavel
P
Hu
Chunyan
C
Dugas
Véronique
V
Goupil
Mathieu
M
Marquis
Miriam
M
de Repentigny
Louis
L
Jolicoeur
Paul
P
D000163:Acquired Immunodeficiency Syndrome / Q000821:virology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002469:Cell Separation; D003713:Dendritic Cells / Q000821:virology; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008264:Macrophages / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039521:CD11c Antigen; D015704:CD4 Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C514837:nef protein, Human immunodeficiency virus 1