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

Inserm U1016, Institut Cochin, Paris, France
Blood (Impact Factor: 9.78). 07/2012; 120(11):2259-68. DOI: 10.1182/blood-2012-03-418681
Source: PubMed

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 TNFα. 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 TNFα 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 TNFα 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.

Download full-text


Available from: Charles-Antoine Dutertre, Jun 29, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Few studies have examined immune activation profiles in patients with advanced HIV-1 subtype C infection or assessed their potential to predict responsiveness to HAART. BioPlex, ELISA, and nephelometric procedures were used to measure plasma levels of inflammatory biomarkers in HIV-1 subtype C-infected patients sampled before and after 6 months of successful HAART (n = 20); in patients failing HAART (n = 30); and in uninfected controls (n = 8). Prior to HAART, CXCL9, CXCL10, β 2M, sTNF-R1, TGF- β 1, IFN- γ , IL-6, TNF, and sCD14 were significantly elevated in HIV-1-infected patients compared to controls (P < 0.01). All of these markers, with the exception of sTNF-R1, were also elevated in patients failing HAART (P < 0.05). The persistently elevated levels of CXCL9, CXCL10, and β 2M in patients failing therapy in the setting of a marked reduction in these markers in patients on successful HAART suggest that they may be useful not only to monitor immune activation during HAART, but also to distinguish between good and poor responders. In the case of sCD14 and TGF- β 1, the levels of these biomarkers remained persistently elevated despite HAART-induced virological suppression, a finding that is consistent with ongoing monocyte-macrophage activation, underscoring a potential role for adjuvant anti-inflammatory therapy.
    Mediators of Inflammation 01/2014; 2014:198413. DOI:10.1155/2014/198413 · 2.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of HIV infection is highly complex and involves numerous actors of the immune system. On the one hand, our immunity has a predominant role in limiting HIV replication and the depletion of its targets, but on the other hand, the persistent infection established by the virus is associated with chronic immune activation and inflammation, potentially resulting in the progressive exhaustion of the host immune resources, and in the onset of non-AIDS-defining comorbidities. The thorough study of HIV pathogenesis is increasingly more challenging. New knowledge together with technological advances offers the possibility to monitor a constellation of cellular immune markers. Here, we discuss the relevance of studying these markers in order to assess the efficacy to control HIV, the inflammatory response to HIV infection, and the alteration and exhaustion of the immune compartments. Monitoring these cellular immune markers is important to reach a deeper understanding of HIV pathogenesis and to perform a comprehensive clinical follow-up of HIV-infected patients.
    Current opinion in HIV and AIDS 03/2013; 8(2):125-31. DOI:10.1097/COH.0b013e32835d08a9 · 4.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Monocytes and myeloid dendritic cells (mDC) are important orchestrators of innate and HIV-specific immune responses, and of the generalized inflammation that characterizes AIDS progression. We investigated, for the first time, monocyte and mDC imbalances in HIV-2+ patients, who typically feature reduced viremia and slow disease progression, despite the recognized ability of HIV-2 to establish viral reservoirs and overcome host restriction factors in myeloid cells. We found a heightened state of monocyte and mDC activation throughout the course of HIV-2 infection (CD14brightCD16+ expansion, increased soluble CD14, HLA-DR and CD86 up-regulation), together with progressive mDC depletion. Importantly, HIV-2+ patients also featured over-expression of the inhibitory molecule PD-L1 on monocytes and mDC, which may act by limiting the production of pro-inflammatory molecules. These data, in a naturally-occurring form of attenuated HIV disease, challenge current paradigms regarding the role of monocytes in HIV/AIDS and open new perspectives regarding potential strategies to modulate inflammatory states.
    The Journal of Infectious Diseases 03/2013; DOI:10.1093/infdis/jit085 · 5.78 Impact Factor