HIV infects activated CD4 ؉ T cells and induces their depletion. Progressive HIV infection leading to AIDS is fueled by chronic immune hyperactivation, mediated by inflammatory cytokines like TNF␣. This has been related to intestinal epithelial damage and microbial LPS translocation into the circulation. Using 11-color flow cytometry, cell sorting, and cell culture, we investigated the numbers and TNF␣ production of fully defined circulating dendritic cell and monocyte populations during HIV-1 infection. In 15 viremic, untreated patients, compared with 8 treated, virologically suppressed patients or to 13 healthy blood donors, circulating CD141 (BDCA-3) ؉ and CD1c (BDCA-1) ؉ dendritic cell counts were reduced. Conversely, CD14 ؉ CD16 ؉؉ monocyte counts were increased, particularly those expressing M-DC8, while classical CD14 ؉؉ CD16 ؊ M-DC8 ؊ monocyte numbers were unchanged. Blood mononuclear cells from viremic patients produced more TNF␣ in response to LPS than those from virologically suppressed patients. M-DC8 ؉ monocytes were mostly responsible for this overproduction. Moreover, M-DC8 ؉ monocytes differentiated in vitro from classical monocytes using M-CSF and GM-CSF, which is increased in viremic patient's plasma. This M-DC8 ؉ monocyte population, which is involved in the pathogenesis of chronic inflammatory diseases like Crohn disease, might thus be considered as a major actor in the immune hyperactivation fueling HIV infection progression. (Blood. 2012;120(11): 2259-2268) IntroductionHIV-1 infection induces the depletion of CD4 ϩ T lymphocytes in blood and lymphoid organs, particularly in the gut-associated lymphoid tissue. [1][2][3] The absence of immune activation during the chronic phase of the infection distinguishes nonprogressive from progressive infections in patients as well as in nonhuman primate models of HIV infection. [4][5][6] Systemic immune activation is correlated to the increased translocation of gut luminal microbial products such as the Gram-negative bacterial lipopolysaccharide (LPS). 7 LPS stimulates the production of proinflammatory cytokines, particularly TNF␣. In HIV-1-infected patients, TNF␣ serum levels increase in correlation with disease progression and drop to normal levels after treatment only in patients with good virologic and immunologic responses. 3,8 By activating the NF-B pathway, TNF␣ induces viral replication in HIV-infected CD4 ϩ T lymphocytes. 3,9 In chronic inflammatory bowel diseases, TNF␣ affects mucosal integrity, leading to microbial product systemic translocation. 10 Granulocyte/macrophage colony-stimulating factor (GM-CSF) and LPS also induce HIV replication in infected myeloid cells. 11,12 GM-CSF and TNF␣ are produced by monocytes and dendritic cells (DCs) after LPS stimulation.During chronic HIV infection, circulating plasmacytoid and myeloid DC (pDC and mDC) numbers are reduced. [13][14][15] Myeloid DCs were mostly studied in HIV-infected patients using CD11c as a marker. Now, they are further subdivided into BDCA-1 ϩ and BDCA-3 ϩ mDC subsets, the latter r...

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