Sirtuins as Interesting Players in the Course of HIV Infection and Comorbidities

Abstract

The sirtuins (SIRTs) are a family of enzymes from the group of NAD⁺-dependent deacetylases. Through the reaction of splitting the acetyl group of various transcription factors and histones they regulate many processes in the organism. The activity of sirtuins is linked to metabolic control, oxidative stress, inflammation and apoptosis, and they also affect the course of viral infections. For this reason, they may participate in the pathogenesis and development of many diseases, but little is known about their role in the course of human immunodeficiency virus (HIV) infection, which is the subject of this review. In the course of HIV infection, comorbidities such as: neurodegenerative disorders, obesity, insulin resistance and diabetes, lipid disorders and cardiovascular diseases, renal and bone diseases developed more frequently and faster compared to the general population. The role of sirtuins in the development of accompanying diseases in the course of HIV infection may also be interesting. There is still a lack of detailed information on this subject. The role of sirtuins, especially SIRT1, SIRT3, SIRT6, are indicated to be of great importance in the course of HIV infection and the development of the abovementioned comorbidities.

Keywords: HAART; HIV; cART; comorbidities; sirtuins.

Figure 1

Scheme of interaction of SIRT1 1 with viral protein Tat [12]. Deacetylation of Tat by SIRT1 causes its reconstitution, preventing the termination of the transcription process at the elongation stage, starting the next HIV transcription cycle. Tat also directly affects SIRT1 by binding to its catalytic domain and thereby blocking deacetylase activity relative to NF-kB, causing production of transcription factors and pro-inflammatory interleukins, among others: IL-2, and as a result, HIV-specific status of chronic immune activation, which allows to integrate the newly formed viral DNA into the host genome. SIRT 1, sirtuin1; IL-2, interleukin 2; Tat, trans-sctivator of transcription; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 2

Scheme of connection between sirtuins, HIV and hepatic metabolism. SIRT3 deacetylates GSK-3β, increasing its activity, which in turn weakens TGF-β signaling. SIRT6, through down-regulation of TGF-β signaling reduces the expression of profibrogenic genes. SIRT1 up-regulates fatty acid oxidation in hepatocytes via the FOXO1/PPARα signaling pathway. Viral protein Vpr acts opposite to SIRT1 to increase expression of genes responsible for the synthesis of fatty acids by increasing SREBP1c activity. SREBP-1c, sterol regulatory element binding protein-1c; FOXO1, forkhead box protein O1; PPARα, peroxisome proliferator-activated receptor α; TGFβ, transforming growth factor β; GSK-3β, glycogen synthase kinase 3 beta.

Figure 3

Scheme of connection between cardiovascular disorders, sirtuins and HIV infection. SIRT1 deacetylate PRMT1 and decrease levels of ADMA—eNOS inhibitor. SIRT1 is also responsible for deacetylation of eNOS, which increases enzyme activity and the production of NO. Endothelial SIRT1 activity against eNOS is promoted by APE1/Ref-1. SIRT1 decrease activity of p53, preventing process of apoptosis in endothelial cells. SIRT1 also deacetylates FOXO1, which has a positive effect on the regulation of apoptosis and cell cycle regulation. Decetylated FOXO1 increases the concentration of CAT and MnSOD. SIRT1 deacetylates Lys-310 in the RelA/p65 complex in NF-κB, suppressing its pro-inflammatory activity in response to OS, and inhibits the synthesis of pro-inflammatory cytokines or thrombotic factors (ICAM-1, VCAM-1). The protective role of SIRT3 is primarily associated with antioxidant protection through the activation of SOD2 and CAT through deacetylation of the FOXO3a and protection against cardiomyocyte apoptosis. In contrast to SIRT3, SIRT4 decreases mitochondrial MnSOD activity. By interacting with AngII, SIRT4 is also a contributing factor to cardiac hypertrophy. SIRT4 also regulates platelet function and the formation of arterial thrombus, by increasing the expression levels of the fibrinolysis inhibitor PAI-1. ROS, reactive oxygen species; OS, oxidative stress; SIRT1, 3, 4, 5, 6, sirtuin 1, 3, 4, 5, 6; eNOS, nitric oxide synthase 3; ADMA, asymetric dimethylarginine; PRMT1, arginine-1 protein transferase; APE1/Ref-1, purinic/apyrmidinic endonuclease 1/redox factor-1; FOXO3, forkhead box O3; VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion molecule 1; CAT, catalase; MnSOD, manganese-dependent superoxide dismutase; GPx, glutathione peroxidase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Ang II, angiotensin II; PAI-1, plasminogen activator inhibitor-1.

Figure 4

Scheme of connection between sirtuins, carbohydrate metabolism and HIV infection. SIRT1, by deacetylation of FOXO1, activates the transcription factors MafA and NeuroD and increases the expression of the insulin gene in pancreatic β cells. By deacetylation of PT-1B, SIRT1 reduces its insulin signal transduction and insulin release inhibitory activity. SIRT1 binds to the promoter for UCP2, inhibits the process of reducing ATP synthesis and restores insulin release from pancreatic β cells. Protease inhibitors act the opposite of SIRT1, they increase the activity of UCP2. SIRT1 down-regulates CRTC2, inhibiting gluconeogenesis during an extended fasting period. Deacetylation of FOXO1 and its co-activator PGC-1α by SIRT1, increases the transcription of gluconeogenesis genes. SIRT1 and SIRT6 deacetylates the HIF-1 by reducing its transcriptional activity, thereby intensifying glycolysis. SIRT2 regulates redox homeostasis by deacetylation of FOXO3a, which increases MnSOD expression and the reduced form of glutathione. In adipocytes, SIRT2 deacetylates PGC-1α, intensifying fatty acid catabolism and gluconeogenesis. SIRT2 also inhibits adipogenesis through deacetylation of FOXO1, promoting its binding to PPARα and reducing its transcriptional activity. SIRT3 deacetylates a key enzyme responsible for liver β-oxidation of fatty acids, LCAD, increasing its activity. Vpr viral protein reduce β-oxidation of fatty acids in the liver and decreases expression of LCAD. The effect of SIRT6 on glucose metabolism is associated with the inhibition of gluconeogenesis via the PGC-1α, which in turn inhibits the expression of PEPCK and glucose 6-phosphatase, associated with gluconeogenesis. SIRT6 also acts by deacylating FOXO1-inhibiting gluconeogenesis. SIRT1,2,3,6, sirtuin 1,2,3,6; HIF1, hypoxia inducible factor-1; LDH, lactate dehydrogenase; CRTC2, CREB regulated transcription coactivator 2; FOXO1, forkhead box protein O1; FOXO3a, forkhead box protein O3a; IL-6, interleukin 6; LCAD, long-chain specific acyl-CoA dehydrogenase; PC1α, peroxisome proliferator activated receptor gamma coactivator 1 alpha; STAT3, signal transducer and activator of transcription 3; UCP2, mtochondrial uncoupling protein 2; PTP1, protein tyrosine phosphatase 1; PPAR-α, peroxisome proliferator-activated receptor alpha; HIF1-α, hypoxia-inducible factor 1-alpha.

Figure 5

Scheme of connection between sirtuins, HIV infection and bone metabolism. SIRT1 deacetylates and up-regulates SOX2, the main factors maintaining the self-renewal and ability to differentiate mesenchymal stem cells in osteoblasts. FOXO1 deacetylation by SIRT1, up-regulates the differentiation of preosteoblast and osteoblast progenitor into osteoblasts. SIRT6 down-regulates Runx2 and Osx genes, responsible for inhibiting blastogenesis and the transition of osteoblasts to osteocytes. SIRT6 up-regulates OPG-RANKL inhibitor, decreasing bone resorption. RANKL, receptor activator for nuclear factor κ B ligand; OPG, osteoprotegerin; FOXO1, forkhead box protein O1; SOX-2, SRY-Box transcription factor 2; Runx2, runt-related transcription factor 2; DKK-1, Dickkopf-related protein 1; MSC, mesenchymal stem cells.

Figure 6

Scheme of connection between sirtuins, kidney disturbances and HIV infection. SIRT1 decreases the activity of NF-κB, STAT3, FOXO4, p53 and PGC-1α in podocytes, preventing excessive OS, inflammation and apoptosis. Deacetylation of PGC-1α by SIRT1 increases its activity, promoting growth and division of mitochondria. PGC-1α also activates PPARα and regulates the processes of β-oxidation of fatty acids, affecting mitochondrial processes. SIRT1 binds to the promoter for angiotensin-converting enzyme 2 (ACE2) and increases its expression, promoting the conversion of Ang to AngII, and regulates the functioning of the RAS system with a positive effect on blood pressure and kidney function. Deacetylation of FOXO4 by SIRT1 prevents activation of BCL-2 gene transcription and the induction of apoptosis in podocytes and tubular cells. SIRT3 prevents mitophage processes and preserves mitochondria integrity by the down-regulation of DRP-1 and the up-regulation of MFF and PINK1. SIRT 1, 3, sirtuin 1, 3; FOXO4, forkhead box O4; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Ang II, angiotensin II; ACE2, angiotensin-converting enzyme 2; PPARα, peroxisome proliferator-activated receptor alpha; PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; STAT3, signal transducer and activator of transcription 3; MFF, mitochondrial fission factor; PINK1, PTEN-induced kinase 1; DRP-1, dynamin-related protein; OS, oxidative stress.

Figure 7

Scheme of connection between sirtuins, neurocognitive disturbances and HIV infection. The Tat protein induces DSB of the DNA strand, leading to OS and apoptosis if the damage is not repaired. SIRT1 activates Ser/ Thr kinase ATM and NBS1 after DSB induction, stabilizing the genome in neurons. SIRT1 is a factor promoting mitochondrial biogenesis through activating PGC-1α. SIRT1 also counteracts the deleterious effect of Tat protein, causing up-regulation of glial fibrillar acid protein in a NF-kB-dependent manner, which in turn causes astrogliosis. SIRT3 prevents disruption of mitochondrial membrane potential and activation of DRP1 and FIS1 factors, promoting excessive mitochondrial cleavage, leading to neuronal death. SIRT3 prevents the excessive division of mitochondria through deacetylation and activation of OPA1 and MFN1, eliminating the excessive activity of DRP and FIS1. SIRT 1, 3, sirtuin 1, 3; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PINK1, PTEN-induced kinase 1; DRP-1, dynamin-related protein; OPA1, optic atrophy 1 protein 1; MFN1, mitochondrial fission 1 protein; OS, oxidative stress.