Pivotal role of M-DC8+ monocytes from viremic HIV-infected patients in TNFα overproduction in response to microbial products

Abstract

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...

IFN-Stimulated Gene LY6E in Monocytes Regulates the CD14/TLR4 Pathway but Inadequately Restrains the Hyperactivation of Monocytes during Chronic HIV-1 Infection

“…We classified purified monocytes according to CD14 and CD16 expression and measured the LY6E levels in these subsets to exclude the possibility that the observed elevation in LY6E levels is due to perturbation in monocyte subsets in HIV infection (32,33 ART-naive subjects with low CD4 count compared with those from subjects with high CD4 count, and this elevation appeared to be decreased after suppression of viral replication by ART (Fig. 2G).…”

“…7A, 7B), indicating that monocytes from HIV patients are in a heightened activation state perhaps owing to persistent viral replication, exposure to homeostatic cytokines, and to microbial products (33)(34)(35). Furthermore, to directly examine the immunosuppressive role of LY6E in HIV infection, CD14…”

MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection

“…Preexposure of monocytes to the TLR7/8 pathway triggered by HIV-1 ssRNA-derived ligands has been considered the causative factor for the increased LPS/TLR4 responsiveness (15). Other studies have focused on the skewed differentiation of monocyte subgroups during HIV-1 infection and observed that proinflammatory CD16 ϩ monocytes and TNF-␣-producing M-DC8 ϩ CD14 ϩ CD16 ϩϩ monocytes were more expanded in chronic HIV-1 infection than in healthy subjects (7,9,17,49). Interestingly, the expansion levels of these cells appear to vary among different reports (7,8,49).…”

“…Preexposure of monocytes to Toll-like receptor 7/8 (TLR7/8) ligands derived from HIV-1 single-stranded RNA (ssRNA) (14,15) and upregulated TLR2 expression on monocytes (16) could enhance the inflammatory responsiveness of these cells. In addition, skewed differentiation of monocytes into proinflammatory CD16 ϩ monocytes and tumor necrosis factor alpha (TNF-␣)-producing M-DC8 ϩ CD14 ϩ CD16 ϩϩ monocytes during chronic HIV-1 infection have been observed in the presence of HIV-1 viremia compared to that observed in HIV-1 seronegative subjects (7,9,17). Effective antiretroviral therapy (ART) successfully suppresses HIV-1 replication but fails to normalize monocyte activation/inflammation (3,(18)(19)(20)(21).…”

“…Monocyte activation and inflammation are commonly found in chronic human immunodeficiency virus type 1 (HIV-1) patients (6)(7)(8)(9)(10)(11). The translocation of bacterial derivatives from the compromised gastrointestinal (GI) tract into the blood observed in chronic HIV-infected subjects (1,5,12) and the hyperresponsiveness of monocytes to lipopolysaccharide (LPS) have been considered impor-tant causative factors for persistent immune activation (6,13).…”