Background: The mechanisms by which CD4⁺ and CD8⁺ T-lymphocytes are affected during HIV-1 infection, as well as the contribution of these cells to the development of AIDS, remain to be elucidated. We have previously reported the development of an AIDS-like disease in CD4C/HIV Transgenic (Tg) mice (wasting, early death, kidney, and lung diseases), which is mainly attributable to nef. These mice show severe immune dysfunctions with a preponderant loss of peripheral CD4⁺ T-cells. The CD4C/HIV Tg mice express HIV-1 gene products in CD4⁺CD8⁺ thymocytes, CD4⁺ T-cells, macrophages, and dendritic cells, which are known to be targeted by HIV-1 in humans.

Methods: Lymph node (LN) CD4⁺ T-cells from Tg and non-Tg mice were purified and expression of surface markers was analyzed by FACS. Cell cycle progression following in vitro activation was assessed by CFSE labeling or by ³H-Thymidine incorporation when assessing allogeneic mixed leukocyte reactions (MLR). In order to investigate the role of CD4⁺ and CD8⁺ T-cells in the Tg-mediated disease, we have bred the CD4C/HIV Tg mice with CD4 (CD4^-/-) or CD8 (CD8^-/-) knockout mice.

Results: We show that an increased number of CD4⁺ T-cells from Tg mice bear an "activated" phenotype, where CD69, CD25, and CD44 levels of expression are increased and CD45Rb reduced. When compared to normal, the Tg CD4⁺ T-cells show a decreased capacity to divide following stimulation with anti-CD3 and anti-CD28. Tg CD4⁺ T-cells were also found to be hypo-responsive during MLR. However, intracellular staining for presence of IL-2 was only slightly decreased following Tg CD4⁺ T-cell activation. Despite these observations, CD4C/HIV Tg mice, which were bred onto a CD4 deficient background, still developed the AIDS-like phenotype. Similarly, in the absence of CD8⁺ T-cells, the Tg mice developed the disease with pathological phenotypes similar to those seen in CD8^+/- Tg mice, with a marked depletion of CD4⁺ T-cells.

Conclusions: Our results suggest that although the Tg CD4⁺ T-cells are affected in number, phenotype and function by the expression of HIV-1 gene products, CD4⁺ T-cells appear to be dispensable to the development of disease. As well, CD8⁺ CTL activity does not appear to be required for the establishment of the AIDS-like disease. Therefore other cell population(s) appear(s) to be contributing significantly to these other phenotypes observed in the Tg mice.