These data underline the potential for early antiretroviral treatment and IFN- alpha treatment to enhance viral control in a larger proportion of patients during the critical stage of primary infection.
In addition to their essential role in adaptive immunity, dendritic cells (DCs) participate in innate immunity. In the context of measles virus (MV) or cytomegalovirus infections, they develop cytotoxic functions that may contribute in vivo to the elimination of virus-infected cells, but that also kill infected and noninfected T lymphocytes. Because the human immunodeficiency virus (HIV) induces T cell depletion through mechanisms that are still obscure, we investigated its ability to trigger DC cytotoxicity. When incubated with HIV, monocyte-derived DCs induced apoptosis in MDA-231 cells, which are sensitive to MV-induced DC cytotoxicity, and in uninfected as well as HIV-infected H9 CD4+ T cell lines. This apoptosis was inhibited by a mixture of FasL, TRAIL, TNF-alpha, and TWEAK inhibitors. Indeed, HIV infection induced or enhanced sensitivity to TRAIL, TNF-alpha, and TWEAK in H9 cells. Moreover, dendritic cells incubated with HIV-1 BAL or a wildtype HIV-1 isolate induced apoptosis in autologous primary CD4+ T lymphocytes, infected or not with a wild-type HIV-1 isolate. Therefore, induction of DC cytotoxicity by HIV may be relevant to in vivo HIV infection. Induction of cytotoxicity in DCs by HIV might contribute to HIV-associated T cell depletion through induction of apoptosis, especially in the early stages of infection. It may also contribute to elimination of infected cells in vivo, thereby enhancing cross-presentation of HIV by DCs. Therefore this new cytotoxic function of DCs may play an important role in innate and adaptive immunity during HIV infection.
A better understanding of the antigen presentation pathways that lead to CD8 ؉ T cell recognition of HIV epitopes in vivo is needed to achieve better immune control of HIV replication. Here, we show that cross-presentation of very small amounts of HIV proteins from apoptotic infected CD4 ؉ T lymphocytes by dendritic cells to CD8 ؉ T cells is much more efficient than other known HIV presentation pathways, i.e., direct presentation of infectious virus or crosspresentation of defective virus. Unexpectedly, dendritic cells also take up actively antigens into endosomes from live infected CD4 ؉ T lymphocytes and cross-present them as efficiently as antigens derived from apoptotic infected cells. Moreover, live infected CD4 ؉ T cells costimulate cross-presenting dendritic cells in the process. Therefore, dendritic cells can present very small amounts of viral proteins from infected T cells either after apoptosis, which is frequent during HIV infection, or not. Thus, if HIV expression is transiently induced while costimulation is enhanced (for instance after IL-2 and IFN␣ immune therapy), this HIV antigen presentation pathway could be exploited to eradicate latently infected reservoirs, which are poorly recognized by patients' immune systems.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
CD14؉ interstitial cells reside beneath the epidermis of skin and mucosal tissue and may therefore play an important role in viral infections and the shaping of an antiviral immune response. However, in contrast to dendritic cells (DC) or blood monocytes, these antigen-presenting cells (APC) have not been well studied. We have previously described long-lived CD14؉ cells generated from CD34 ؉ hematopoietic progenitors, which may represent model cells for interstitial CD14؉ APC. Here, we show that these cells carry DC-SIGN and differentiate into immature DC in the presence of granulocyte-macrophage colony-stimulating factor. We have compared the CD14 ؉ cells and the DC derived from these cells with respect to dengue virus and human immunodeficiency virus type 1 (HIV-1) infection. Both cell types are permissive to dengue virus infection, but the CD14؉ cells secrete the anti-inflammatory cytokine interleukin 10 and no tumor necrosis factor alpha. Regarding HIV, the CD14 ؉ cells are permissive to HIV-1, release higher p24 levels than the derived DC, and more efficiently activate HIV Pol-specific CD8؉ memory T cells. The CD14 ؉ DC precursors infected with either virus retain their DC differentiation potential. The results suggest that interstitial CD14 ؉ APC may contribute to HIV-1 and dengue virus infection and the shaping of an antiviral immune response.
IntroductionDendritic cells (DCs) are professional antigen-presenting cells that can induce optimal activation of naive T lymphocytes. They have developed unique cross-presentation pathways allowing major histocompatibility complex (MHC) class I-restricted presentation of antigens of exogenous origin, taken up by endocytosis or phagocytosis. Cross-presentation is crucial for the stimulation of CD8 ϩ T lymphocytes and therefore induction of immunity and tolerance to antigens that are not directly synthesized in the cytosol of DCs, such as antigens from other tissues, from tumors or from pathogens that do not infect DCs predominantly. [1][2][3][4][5] DCs are required for cross-presentation in vivo. 6 So understanding the mechanism of cross-presentation by DCs is an important issue to provide optimized immune therapies.DCs participate in the phagocytic clearance of apoptotic debris, from which they cross-present antigens, 7 a phenomenon observed in vivo. 8,9 Apoptosis was thought to be tolerogenic, whereas necrosis was truly immunogenic through the release of nuclear or cytosolic molecules that serve as endogenous adjuvants. 10,11 Indeed, cross-tolerization of tissue-restricted Ag is enhanced when proapoptotic stimuli are included, and conversely, is prevented by expression of an antiapoptotic molecule. 12 Moreover, a DC-specific deficiency in uptake of apoptotic material inhibits cross-tolerization in vivo. 13 However, cross-presentation from apoptotic cells can lead to immunogenicity in the presence of proinflammatory signals, CD4 help, 14,15 infection, 16 through the surface expression of ER molecules, such as calreticulin, or through the release of HMGB1 by apoptotic cells. 17 The focus in the past years has been on the mechanism of cell death leading to cross-presentation. The current concept of "death-defying immunity" is fascinating and must have physiologic relevance. 15,18 But is death necessary to induce cross-presentation?We have shown that cross-presentation of HIV antigens from apoptotic infected CD4 ϩ T lymphocytes, which are the main targets of viral replication, is a very efficient process in vitro. Surprisingly, transfer and cross-presentation of HIV antigens from live infected CD4 ϩ T lymphocytes by human monocyte-derived DCs were found to be as efficient as cross-presentation from apoptotic cells. 19 This novel mechanism of cross-presentation is currently not fully characterized but needs cell-to-cell contact, similarly to the "nibbling" process described previously that gave rise to tumor antigen cross-presentation. 20,21 Although crosspresentation from live cells led to efficient restimulation of memory HIV-specific CD8 ϩ T lymphocytes from HIV-infected patients, 19 it is still unknown whether this mechanism could apply to naive T lymphocytes in vivo. Cross-presentation of antigens from live cells has never been taken into account, although live cells may be a major source of antigen in vivo. It was important to establish whether this new cross-presentation mechanism was only an artifact found ...
BackgroundConventional serological tests, using total soluble proteins or a cocktail of recombinant proteins from T. cruzi as antigens, are highly sensitive for Chagas disease diagnosis. This type of tests, however, does not seem to be reliable tools for short- and medium-term monitoring of the evolution of patients after antiparasitic treatment. The aim of the present study was to search for immunological markers that could be altered in the sera from Chagas disease patients after benznidazole treatment, and therefore have a potential predictive diagnostic value.MethodsWe analyzed the reactivity of sera from chagasic patients during different clinical phases of the disease against a series of immunodominant antigens, known as KMP11, PFR2, HSP70 and Tgp63. The reactivity of the sera from 46 adult Chronic Chagas disease patients living in a non-endemic country without vector transmission of T. cruzi (15 patients in the indeterminate stage, 16 in the cardiomiopathy stage and 16 in the digestive stage) and 22 control sera from non-infected subjects was analyzed. We also analyzed the response dynamics of sera from those patients who had been treated with benznidazole.ResultsRegardless of the stage of the sickness, the sera from chagasic patients reacted against KMP11, HSP70, PFR2 and Tgp63 recombinant proteins with statistical significance relative to the reactivity against the same antigens by the sera from healthy donors, patients with autoimmune diseases or patients suffering from tuberculosis, leprosy or malaria. Shortly after benznidazole treatment, a statistically significant decrease in reactivity against KMP11, HSP70 and PFR2 was observed (six or nine month). It was also observed that, following benznidazole treatment, the differential reactivity against these antigens co-relates with the clinical status of the patients.ConclusionsThe recombinant antigens KMP11, PFR2, Tgp63 and HSP70 are recognized by Chagas disease patients' sera at any clinical stage of the disease. Shortly after benznidazole treatment, a drop in reactivity against three of these antigens is produced in an antigen-specific manner. Most likely, analysis of the reactivity against these recombinant antigens may be useful for monitoring the effectiveness of benznidazole treatment.
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