Manipulation of ILC function and survival by human and simian immunodeficiency viruses

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Chronic inflammation caused by microbial translocation from the gastrointestinal tract into the systemic circulation drives AIDS progression in HIV-1 infected individuals. In striking contrast, chronic immune activation is absent in nonpathogenic SIV infections of natural host species. The mechanisms underlying the destruction of intact intestinal mucosal barrier function and the different clinical outcomes of HIV-1 and well-adapted SIV infections are still poorly understood. Recent data suggest, however, that effects of HIV-1 infection on innate lymphoid cells (ILCs) play an important role in the pathogenesis of AIDS. Most notably, group 3 ILCs (ILC3s) that are essential for maintenance of intestinal barrier function and homeostasis are rapidly depleted in acute HIV-1 infection. Thus, loss of ILC3s most likely plays a key role in the permanent damage of the intestinal mucosal barrier. In the present proposal, we thus want to determine how HIV-1 and other primate lentiviruses affect ILC3 function and survival. It has been suggested that the production of type I interferons (IFNs) by plasmacytoid dendritic cells or MHC-II/TCR-CD3-mediated interactions of ILCs with conventional CD4+ T cells regulate the fate and activity of intestinal ILCs. We have shown that HIV-1 induces higher levels of type I IFN than HIV-2 or simian immunodeficiency viruses (SIVs) and that only the latter are capable of downmodulating the CD3 T cell receptor from the cell surface. Through comparative analyses of HIV-1 with less pathogenic HIV-2 and "non-pathogenic" SIV clones or specific mutants thereof, we will determine the mechanisms responsible for the depletion of ILC3s. Furthermore, we will analyze whether some primate lentiviruses might directly infect and manipulate some types of ILCs. Finally, we will determine whether the accessory viral Vpr, Vpu or Nef proteins might modulate cell surface receptors (such as TCR-CD3) or cytokine expression (e.g. IFNs) by virally infected CD4+ T cell, macrophages or plasmacytoid dendritic cells to modulate ILC function. The results will provide new information on the mechanisms underlying the depletion of ILC populations that are critical for effective innate immunity and the maintenance of intact intestinal barrier function. This knowledge might help to develop new strategies to prevent damaging chronic immune activation in HIV-infected individuals.