Grant: Operating Grant - PA: HIV/AIDS Bridge Funding - Biomedical/Clinical Stream

Depletion of CD4+ T cells is the hallmark of HIV infection and is almost always associated with activation of these cells. Efforts to understand how these human cells are depleted have led to a number of interesting, but often discordant, results and no consensus has yet been reached on the mechanisms by which CD4+ T cells are depleted. In particular, we still do not know the molecular pathways critical for CD4+ T cell depletion in vivo. One of the reasons for this situation is that, most of these experiments are conducted on CD4+ T cells manipulated in vitro and that experiments on HIV-infected cells from patients are notoriously difficult. Clearly, novel approaches are needed to get further insights into this problem. Over the last few years, we have generated a mouse model of AIDS by expressing HIV-1 genes in mice. These mice develop all the immune manifestations of AIDS, notably a progressive loss of CD4+ T cells, as in human AIDS. We have recently found that specific signalling pathways are significantly altered in CD4+ T cells of these Tg mice. We plan to further analyze the molecular defects of some critical molecules of one of this pathway. We have also found that manipulation of this pathway can rescue CD4+ T cell depletion in mice. We plan to determine which are the critical members of this pathway which allow a rescue of CD4+ T cell depletion and activation. Finally, we plan to determine whether the very specific and novel molecular defects that we are detecting in mouse CD4+ T cells can also be observed in HIV-infected primary unmanipulated human CD4+ T cells. As shown, this animal model is helping us to ask novel and relevant questions and to design novel experiments to understand the pathways of CD4+ T cell loss in AIDS.