HIV-1 decreases Nrf2/ARE activity and phagocytic function in alveolar macrophages

Abstract

Respiratory complications occur frequently in individuals living with human immunodeficiency-1 virus (HIV) infection, and there is evidence that HIV-related oxidative stress impairs alveolar macrophage immune function. We hypothesized that nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that activates the antioxidant response element (ARE) and regulates antioxidant defenses, has an important role in alveolar macrophage (AMs) immune dysfunction in individuals with HIV infections. To test that hypothesis, we analyzed human monocyte-derived macrophages (MDMs) that were either infected with HIV-1 or were exposed to the HIV-related proteins gp120 and Tat ex vivo and determined that either stress affected the expression of Nrf2 and the Nrf2-ARE-dependent genes for NAD(P)H dehydrogenase, quinone 1 () and glutamate-cysteine ligase, catalytic subunit (). We then determined that the expression of Nrf2, NQO1, and GCLC was significantly decreased in primary AMs isolated from HIV-1 transgenic rats. In parallel, treating a rat macrophage cell line (NR8383 cells) with the HIV-related proteins gp120 or Tat similarly decreased the gene and protein expression of Nrf2, NQO1, and GCLC. Further, phagocytic function was decreased in both human MDMs infected with HIV-1 and primary AMs from HIV-1 transgenic rats. Importantly, treating HIV-1-infected human MDMs or AMs from HIV-1 transgenic rats with sulforaphane (SFN, an Nrf2 activator) significantly improved their phagocytic function. The salutary effects of SFN were abrogated by silencing RNA to Nrf2 in wild-type rat macrophages. Our findings demonstrate that HIV-1 infection and exposure to HIV-1-related proteins inhibit Nrf2-ARE activity in the AMs and impair their phagocytic function. Treatments targeted at increasing Nrf2-ARE activity could, therefore, enhance lung innate immunity in people living with HIV-1.

The role of Nrf2 transcription factor in viral infection

“…These proteins decrease the expression of two downstream antioxidant enzymes GCLC and NQO1 in NR8383 cells (a rat alveolar macrophage cell line) that lead to oxidative stress‐related distribution in phagocytic alveolar macrophage function. Such a mechanism has also been observed in human MDMs infected with the HIV‐1 virus …”

“…55 HIV-1 infection and HIV-related proteins gp120 or Tat supress Nrf2-ARE pathway activity in human MDMs. 56 HIV-Tat activates the Nrf2/ARE pathway in human neuroblastoma cells 57 siKeap1(overexpression Nrf2) repressed Tat-induced HIV-1 LTR transactivation in HeLa-derived MAGI cells 58 RT activates the Nrf2/ARE pathway in BALB/c mice splenocyte cell culture 62 Gp120 induces a Nrf2-dependent gene, multidrug resistant protein 1 (Mrp1) 63 Replication of virus seems to inhibit the Nrf2/ARE pathway in the brain 64 Marburg mVP24 induces the Nrf2/ARE pathway via interaction with Keap1 75 suppression of nrf2 significantly increased the levels of NF-kB, TNF-a, and MMP-9 68 mVP24 activates the NF-κB pathway by prevention of IKKβ degradation by Keap1 80 The MARV infection is associated with better survival and lower viral replication in Nrf2-deficient mice compared to wild-type animals 81 DENV Activation of Nrf2 induces CLEC5A upregulation and TNF-α production during DENV infection 88 Nrf2 modulated ROS-induced immune and apoptotic responses in DENV-infected human Mo-DC 89 HBV HBV activates the Nrf2/ARE-regulated genes via c-Raf-MEK-ErK signaling pathway 93 HBV Increased amount and activity of the proteasome subunit PSMB5 and vice versa decreased activity of the immunoproteasome, Consequently, inhibited the immune system 98 HBV effect on the reprogramming of the glucose metabolism in hepatocytes, which may be of importance in the development of HBV-associated hepatocarcinoma 103 HCV HCV infection through the Ca 2+ signaling and elevated levels of ROS in mitochondria activated the Nrf2 106 In HCV infection delocalization of sMaf proteins has a negative effect on Nrf2/ARE signaling pathway 107 E1, E2, Core, NS4B and NS5A viral proteins involved in activation of Nrf2/ARE signaling pathway 108 KHSV ROS and signaling axis consisting of the Src, PI3-K and PKCζ kinases role in activation nrf2 in early infection 118 COX-2/PGE2/PKCζ axis role in activation nrf2 in latency infection 119 Nrf2 activation up regulates the expression several proteins with antiapoptotic, proinflammatory, pro-angiogenic and proliferative functions 120 The inhibition of autophagy by v-FLIP activates nrf2 during latency infection 121 Other Viruses Nrf2-dependent HO-1 enzyme inhibits Zika virus replication in primary hMDM cells 124 Activation of Nrf2 is associated with increased survival of HCMV and the establishment of chronic inflammation CVB3 down-regulated the expression levels of Nrf2 125 Activat...…”

“…Such a mechanism has also been observed in human MDMs infected with the HIV-1 virus. 55,56 The HIV-Tat proteins activates the Nrf2/ARE pathway in human SH-SY5Y neuroblastoma cells, mediated by the induction of spermine oxidase through NMDA Receptor (a glutamate receptor in nerve cells) that cause increase AREdriven genes expression and many anti oxidative response enzymes, such as NQO1, CAT, SOD1, SOD2, and HO-1. 57 Also, Tat increased nuclear Nrf2 levels in HeLa-derived MAGI cells which it is associated with decreased Tat-mediated HIV-1 LTR transactivation.…”

Hydrogen sulfide in physiology and pathogenesis of bacteria and viruses

“…At molecular level HIV‐1 infection or exposure to HIV‐1 related proteins downregulates the Nuclear factor‐erythroid‐2 p45 related factor 2‐Antioxidant Response Element (Nrf2/ARE) pathway, leading to reduced expression of antioxidant genes . Nrf2 is a constitutive transcription factor and master regulator of the antioxidant response .…”

Nrf2 Activator PB125®as a Potential Therapeutic Agent Against COVID-19

“…Among the types of virus studied are influenza virus, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) [9][10][11][12][13]. The phenomenon is also seen in non-respiratory viruses including Dengue virus (DENV) [14], rotavirus [15], herpes simplex virus [16], Zika virus [17], and HIV [18], suggesting that regulation of oxidative stress may be a need common to most, if not all viruses, and that Nrf2 activators may offer multiple ways to regain control of important pathways to increase resistance and slow viral replication. We recently described a phytochemical composition, PB125, that potently activates Nrf2 by controlling multiple steps involved in the process, especially via the Akt1/PI3K/GSK3/Fyn pathway [19].…”