Research Article: HIV replication is associated to inflammasomes activation, IL-1β, IL-18 and caspase-1 expression in GALT and peripheral blood

Date Published: April 19, 2018

Publisher: Public Library of Science

Author(s): Manuel Gerónimo Feria, Natalia Andrea Taborda, Juan C. Hernandez, Maria Teresa Rugeles, Iratxe Puebla.

http://doi.org/10.1371/journal.pone.0192845

Abstract

Human immunodeficiency virus (HIV) promotes an inflammatory process, leading to the progressive loss of the functional capacity of the immune system. The HIV infection induces alterations in several tissues, but mainly in the gut-associated lymphoid tissue (GALT). However, the degree of GALT deterioration varies among infected individuals. In fact, it has been shown that HIV-controllers, who spontaneously control viral replication, exhibit a lower inflammatory response, and a relative normal frequency and function of most of the immune cells. Inflammasomes are molecular complexes involved in the inflammatory response, being NLRP1, NLRP3, NLRC4, AIM2 and Pyrin inflammasomes, the best characterized so far. These complexes regulate the maturation of cytokines of the IL-1 family, including IL-1β and IL-18. These cytokines have been associated with immune activation and expansion of HIV target cells, promoting viral replication. Interesting, some reports indicate that HIV induces the activation of the NLRP3 inflammasome, but the role of this, and other inflammasomes during HIV infection, especially in GALT, remains unclear.

To compare the relative expression of inflammasome components and the proinflammatory response related to their activity, between HIV-progressors and HIV-controllers.

GALT biopsies and peripheral blood mononuclear cells (PBMCs) from 15 HIV-controllers and 15 HIV-progressors were obtained. The relative expression of the following inflammasome components were evaluated by RT-PCR: NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1β and IL-18. In addition, plasma concentration of IL-18 was evaluated as an indicator of baseline proinflammatory status. Finally, in supernatants of PBMCs in vitro stimulated with inflammasome agonists, the concentrations of IL-1β and IL-18 were quantified by ELISA.

HIV-progressors exhibited higher expression of IL-1β, IL-18 and caspase-1 genes in GALT and PBMCs compared with HIV-controllers. In addition, HIV-progressors had also increased expression of ASC in PBMCs. When plasma levels were evaluated, IL-18 was increased in HIV-progressors. Interesting, these patients also showed an increased production of IL-1β in supernatants of PBMCs stimulated in vitro with the agonists of AIM2, NLRP1 and NLRC4 inflammasomes. Finally, the expression of caspase-1, NLRP1, IL-1β and IL-18 in GALT or peripheral blood was correlated with CD4+ T-cell count and viral load.

Our results suggest that during HIV-infection, the required signals to induce the expression of different components of the inflammasomes are produced, both in GALT and in periphery. The activation of these molecular complexes could increase the number of target cells, favoring HIV replication and cell death, promoting the disease progression.

Partial Text

The pathogenesis of HIV involves a complex interaction between several viral and host factors. So far, it is recognized that the gut-associated lymphoid tissue (GALT) is the main affected organ, as a consequence of the massive elimination of CD4+ T-cells, in particular Th17 cells that play an essential role in the mucosa homeostasis [1, 2]. The elimination of these and other cells such as enterocytes [3–5], induces structural damage in GALT, allowing microbial translocation from the intestinal lumen to systemic circulation, promoting excessive immune activation [6]. This state, currently recognize as the main immunopathogenic mechanism during HIV infection, is established during the acute phase and remains throughout the course of the infection, leading to cell exhaustion and activation-induced apoptosis [7]. Myeloid cells, including monocytes/macrophages and dendritic cells, are also affected by immune activation, as there is an increased level of microbial ligands recognized by Toll (TLR) and NOD (NLR) receptors inducing activation of NF-κB and the gene expression of proinflammatory cytokines such as IL-1β and IL-18 [8, 9]. In addition, endosomal TLR7 and TLR8 could detect HIV, increasing the inflammatory response [10, 11]. IL-1β and IL-18 are involved in the differentiation of naïve CD4+ T cells to Th1 and Th17 profiles [12–14], increasing even more the immune activation, and promoting viral replication since these cells are viral targets; in fact, these cytokines are increased in plasma of infected patients [15, 16], suggesting their involvement in HIV pathogenesis [10, 11].

HIV is characterized by an unregulated inflammatory response and the consequent immune exhaustion [27]. Inflammasomes could be one of the immune components involved in this process. They are important in the regulation of the caspase-1 activity to induce the proteolytic maturation of the IL-1β and IL-18. These proinflammatory cytokines are particularly increased in HIV infected individuals, suggesting their role in AIDS progression [15, 28]. In fact, it has been shown that HIV has the ability to activate the NLRP3 inflammasome [15]; however, the definite role of this, and other inflammasomes during the pathogenesis of HIV is still unclear. Here, we evaluated the role of different inflammasomes in the pathogenesis of this infection, by studying two different groups of infected patients: HIV-controllers and HIV-progressors.

 

Source:

http://doi.org/10.1371/journal.pone.0192845

 

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