HIV-1 infection causes depletion and/or dysfunction of distinct CD4+ T cell subsets and may affect these differently. Regulatory CD4+ CD25Hi Foxp3+ T cells (Treg) represent a distinct CD4+ T cell subset with suppressor activity. These cells play an important role in the regulation of self-tolerance and autoimmunity, and in the regulation of immune responses against cancerous tumors and pathogens. During HIV infection, several studies have reported abnormalities of CD4+ Treg in blood and/or lymphoid organs. However, it has not been possible to firmly establish whether Treg are beneficial or pathogenic to the host during HIV infection. Because much remains to be learned about Treg in the context of HIV-1 infection, and because the mouse has so far been one of the best models to study the biology of Treg, we hypothesize that a study on Treg in a mouse model of AIDS may facilitate our understanding of their role in this disease. In the present study, we used the CD4C/HIVNef transgenic (Tg) mouse model to investigate Treg disturbances and characteristics. These Tg mice express Nef under the regulation of the upstream elements of the human CD4 gene and develop a very severe AIDS-like disease. In particular, they exhibit abnormal development of thymic CD4+ T cells, loss and enhanced apoptosis of CD4+ T cells and activation of CD4+ and CD8+ T cells. We report that HIV-1 Nef in this Tg mouse model causes depletion of total CD4+ T cells, but preserves and relatively enriches CD4+ Treg. We found that Nef-mediated CD4+ Treg enrichment is the direct result of Nef expression in CD4+ T cells and occurs independently of Nef-induced lymphopenia. Tg CD4+ Treg accumulation likely results from multiple mechanisms: lower apoptosis, enhanced cell division and increased generation from precursors. Interestingly, Tg CD4+ Treg enrichment could be reversed by enhancing Lck activity. Most importantly, we show that, in contrast to Tg helper CD4+ T cells which have lost their function, Nef-expressing CD4+ Treg retain their regulatory function in vitro and also in vivo, under some settings. In particular, we found that Treg prevent expansion of Tg B and non-Treg T cells in vivo. Our study reveals that Nef affects distinct CD4+ T cell subsets differently and uncovers the high proliferative potential of B and non-Treg T cells in this mouse model.


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