Selective Expression of Human Immunodeficiency Virus Nef in Specific Immune Cell Populations of Transgenic Mice Is Associated with Distinct AIDS-Like Phenotypes

Abstract

ABSTRACT 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.