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

Abstract

BackgroundHuman 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.ObjectiveTo compare the relative expression of inflammasome components and the proinflammatory response related to their activity, between HIV-progressors and HIV-controllers.MethodsGALT 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.ResultsHIV-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.ConclusionOur 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.

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

“…Our observations highlight only mechanisms involved in the blood of HIC compared to cART patients. However, HIV infection also induces the expression of different components of inflammasomes in GALT (46), and both the immune regulation and delayed progression to AIDS were associated with a particular activation phenotype of T cells in GALT from HIC (47). Furthermore, in HIV infection immune activation and inflammation were also associated with immunometabolism reprogramming through the use of glucose and fatty acids (48).…”

Factores inmunológicos relacionados con VIH-1 en pacientes colombianos

“…Lo cual apunta a que estas citoquinas tienen un papel importante durante la infección por vih-1. Asimismo, se ha reportado que los pacientes progresores presentan mayor expresión transcripcional de algunos componentes de los inflamasomas, así como mayor secreción de il-1β e il-18, comparados con los controladores (11). Estos resultados indican que los inflamasomas tienen un papel importante durante la infección por vih-1.…”

“…En este sentido, estudios previos muestran que los individuos con vih-1 presentan una disminución en los niveles e hdl, una lipoproteína con propiedades inmunomodularoras (12). Asimismo, se ha encontrado que los niveles de hdl se correlacionan con parámetros de la infección, como el conteo de linfocitos t cd4+ y la carga viral, lo que apunta a que la hdl podría tener un impacto durante la infección por vih-1 (11,13). Recientemente, en un estudio con población de Medellín, Colombia, la hdl se correlacionó con la expresión transcripcional de nlrp3, así como con otros componentes de los inflamasomas y sus productos (14).…”

Initial periodontal treatment affects nucleotide-binding domain leucine-rich repeat-containing protein 3 inflammasome priming in peripheral blood mononuclear cells

“…The cDNA was treated with RNase H and purified using the QIAprep Spin Miniprep Kit (Qiagen). The primer sequences used were as follows: IL-1β forward, 5′-GCTGGAGGACTTT AAGGGTTAC-3′, and reverse, 5′-GATGTCTGGGTCTTGGTTCTC-3′; NLRP3 forward, 5′-AGCACCAGCCAGAGTCTAAC-3′, and reverse, 5′-CCCCAACCACAATCTCCGAAT-3′; ASC forward, 5′-AACCCAAGCAA GATGCGGAAG-3′, and reverse, 5′-TTAGGGCCTGGAGGAGCAAG-3′; Caspase-1 forward, 5′-CAAGGGTGCTGAACAAGG-3′, and reverse, 5′-GGGCATAGCTGGGTTGTC-3′; glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forward, 5′-CATGTTCGTCATGGGTGTGA-3, and reverse, 5′-CAGGGGTGCTAAGCAGTTGG-3′ (Feria, Taborda, Hernandez, & Rugeles, 2018;Tzach-Nahman et al, 2017). Comparative quantification by PCR was performed with SYBR Premix Ex Taq using the Mx3000 P qPCR System (Agilent technologies, Santa Clara, CA).…”