Systemic inhibition of myeloid dendritic cells by circulating HLA class I molecules in HIV-1 infection

Soluble HLA class I molecules were highly upregulated in progressive HIV-1 infection as determined by quantitative Western blots. This was associated with strong increases of intracellular expression of HLA class I isoforms in dendritic cells and monocytes. Using mixed lymphocyte reactions, we found that soluble HLA class I molecules effectively inhibited the antigen-presenting properties of dendritic cells, however, there was no significant influence of HLA class I molecules on the cytokine-secretion properties of these cells. The immunomodulatory effects of soluble HLA class I molecules were mediated by interactions with inhibitory myelomonocytic MHC class I receptors from the Leukocyte Immunoglobulin Like Receptor (LILR) family.During progressive HIV-1 infection, soluble HLA class I molecules can contribute to systemic immune dysfunction by inhibiting the antigen-presenting properties of myeloid dendritic cells through interactions with inhibitory myelomonocytic HLA class I receptors.HIV-1 infection leads to massive immune activation that results from direct stimulation of immune cells by HIV-1 antigens, the release of large amounts of pro-inflammatory cytokines, and the systemic circulation of bacterial polysaccharide antigens after translocation from intestinal mucosal tissues [1]. This immune activation can cause counter-regulatory activities of inhibitory components of the immune system, such as increased recruitment of regulatory T cells [2], upregulation of inhibitory receptors on antigen-specific T cells [3,4], and enhanced expression of immunoregulatory receptors on dendritic cells [5,6]. These mechanisms may in part protect the host against immune pathology by limiting over activation of the immune system, but might also contribute to viral persistence by propagating immune dysfunction. Identifying immunomodulatory mechanisms that contribute to this functional disarray between stimulatory and inhibitory immunological pathways is an important step in unde