Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors

Peripheral blood mononuclear cells from patients with human immunodeficienc y virus (HIV) infection exhibit a progressively marked decrease in the prod uction of virus-induced interferon (IFN)-alpha, a finding that correlates w ith and is highly predictive of disease progression and opportunistic infec tions. The major IFN-a producing population has recently been defined as th e precursor to type 2 dendritic cells (pDC2) or plasmacytoid DC (pDC). Usin g four-color flow cytometry, we have enumerated the pDC2 vs non-IFN-a produ cing myeloid DC1 in peripheral blood from HIV-infected patients and healthy controls and related these values to CD4 cell numbers, viral load, and fun ctional activity. The patients had reductions in the numbers of both pDC2 ( lin(-)/HLA-DR+/CD123(bright)) and DC1 (lin1(-)/HLA-DR+/CD123(dim)/CD11c(+)) , both at an absolute level and as a percentage of cells. The decreases wer e most evident in patients with decreased CD4 levels. Viral load correlated with the functional frequency of the IFN producing cells but riot with abs olute pDC2 levels. Using intracellular flow cytometric analysis for IFN-alp ha, the patients were demonstrated to have fewer pDC2, as well as a lower p ercentage of responding cells among those remaining. We conclude that defic ient production of IFN-alpha by pDC2 from HIV-infected patients results fro m both selective loss of these cells and their qualitative dysfunction. Giv en the central role of DC, and in particular, DC2, in linking innate and ad aptive immune responses, these qualitative and quantitative changes in pDC2 are likely to be key contributors to HIV pathogenesis. (C) 2001 Academic P ress.