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...

In mice, CD8α+ myeloid dendritic cells (mDC) optimally cross-present Ags to CD8+ T cells and respond strongly to TLR3 ligands. Although equivalent DC have been identified by comparative genomic analysis and functional studies in humans as XCR1+CD141 (BDCA-3)+Clec9A+cell adhesion molecule 1+ mDC, and in sheep as CD26+ mDC, these cells remained elusive in nonhuman primates. To remedy this situation, we delineated precisely DC and monocyte populations by 12-color flow cytometry and transcriptomic analyses in healthy rhesus macaques. We identified a new mDC population, with strong phenotypic and transcriptional homology to human CD141+ and murine CD8α+ mDC, including XCR1 membrane expression as a conserved specific marker. In contrast, high CD11c expression was not characteristic of mDC in macaques, but of CD16+ monocytes. Like their human and murine homologs, simian XCR1+ mDC had much stronger responses to TLR3 stimulation than other myeloid cells. The importance of this new mDC population was tested in SIVmac251 infection, the most relevant animal model for pathogenic HIV-1 infection and vaccination. This population increased sharply and transiently during acute infection, but was reduced in blood and spleen during advanced disease. The identification of XCR1+ mDC in rhesus macaques opens new avenues for future preclinical vaccinal studies and highlights XCR1 as a prime candidate for targeted vaccine delivery.