Induction of OAS gene family in HIV monocyte infected patients with high and low viral load

HIV‐infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS. We hypothesized that retroviral infection would lead to dysregulation of hepatic pathways of SMX biotransformation, as well as pathway alterations in common with SLE that could contribute to drug HS risk. We characterized hepatic expression profiles and enzymatic activities in an SIV‐infected macaque model of retroviral infection, and found no evidence for dysregulation of sulfonamide drug biotransformation pathways. Specifically, NAT1,NAT2,CYP2C8,CYP2C9,CYB5R3,MARC1/2, and glutathione‐related genes (GCLC,GCLM,GSS,GSTM1, and GSTP1) were not differentially expressed in drug naïve SIVmac239‐infected male macaques compared to age‐matched controls, and activities for SMX N‐acetylation and SMX hydroxylamine reduction were not different. However, multiple genes that are reportedly over‐expressed in SLE patients were also up‐regulated in retroviral infection, to include enhanced immunoproteasomal processing and presentation of antigens as well as up‐regulation of gene clusters that may be permissive to autoimmunity. These findings support the hypothesis that pathways downstream from drug biotransformation may be primarily important in drug HS risk in HIV infection.

show abstract

“…Up‐regulated in monocytes of HIV‐infected patients with high viral loads; inversely proportional to CD4 + lymphocyte counts (Fagone et al. )…”

Section: Resultsmentioning

confidence: 99%

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

Wong¹,

Johnson

Friedrich

et al. 2017

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…The OAS proteins family are IFN‐stimulated proteins, which have key roles in innate immune responses. They catalyze the synthesis of 2′‐5′‐linked oligoadenylates to activate RNAse L and degrade the viral and cellular RNAs . Also, it has been stated that the increase of the 2′‐5′‐oligoadenylate enzyme synthetase can be used as a prognostic indicator for increasing the risk of HIV infection progression to AIDS .…”

Section: Discussionmentioning

confidence: 99%

“…Also, it has been stated that the increase of the 2′‐5′‐oligoadenylate enzyme synthetase can be used as a prognostic indicator for increasing the risk of HIV infection progression to AIDS . The expressions of the OAS gene family increase in the monocytes of the untreated HIV‐positive (PBMCs tissue) in response to IFN α and β produced by the immune system against virus . The downregulation of IFNG , OAS1 , and OAS2 in the treated HIV‐positive subjects confirms that the interferon signaling pathways and their involved proteins should be considered as the prominent targeted pathways in the treatment of HIV.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Also, it has been stated that the increase of the 2′-5′-oligoadenylate enzyme synthetase can be used as a prognostic indicator for increasing the risk of HIV infection progression to AIDS. 19 The expressions of the OAS gene family increase in the monocytes of the untreated HIV-positive (PBMCs tissue) in response to IFN α and β produced by the immune system against virus. 19,20 The downregulation of IFNG, OAS1, and OAS2…”

Section: Discussionmentioning

confidence: 99%

“…19 The expressions of the OAS gene family increase in the monocytes of the untreated HIV-positive (PBMCs tissue) in response to IFN α and β produced by the immune system against virus. 19,20 The downregulation of IFNG, OAS1, and OAS2…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Reconnaissance of the candidate genes involved in the pathogenesis of human immunodeficiency virus and targeted by antiretroviral therapy

Mozhgani

Ghobadi

Rad

et al. 2019

Journal of Medical Virology

View full text Add to dashboard Cite

The expression levels of many genes change after treatment of human immunodeficiency virus (HIV)‐infected subjects by antiretroviral drugs. High‐throughput analysis of tremendous datasets led to the discovery of genes that are implicated in the treatment pathways. In this study, we performed a gene‐enrichment analysis after determining the differentially expressed genes (DEGs) between untreated HIV‐positive and HIV‐negative subjects and also between treated HIV‐positive subjects with antiretroviral therapy (ART; who receiving nucleoside reverse transcriptase inhibitor–based ART) and untreated HIV‐positive cases in the peripheral blood mononuclear cells (PBMCs), adipose, and muscle tissues. In sum, the genes that activate inflammatory, immune response, proliferation, metabolism, and viral involvement pathways have different expression patterns in the untreated HIV‐positive subjects and treated HIV‐positive cases. Moreover, the expression levels of the genes including ACLY, ALDH18A1, HADHA, and YARS in the PBMCs tissue and HBEGF, PKN3, DEGS2, and EDN3 in the fat tissue were found to be different in the HIV‐infected patients, which can be considered as new biomarkers for HIV infection.

show abstract

Activation of Toll‐like receptor 3 inhibits HIV infection of human iPSC‐derived microglia

Wang,

Liu,

Wang

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

As a key immune cell in the brain, microglia are essential for protecting the central nervous system (CNS) from viral infections, including HIV. Microglia possess functional Toll‐like receptor 3 (TLR3), a key viral sensor for activating interferon (IFN) signaling pathway‐mediated antiviral immunity. We, therefore, studied the effect of poly (I:C), a synthetic ligand of TLR3, on the activation of the intracellular innate immunity against HIV in human iPSC‐derived microglia (iMg). We found that poly (I:C) treatment of iMg effectively inhibits HIV infection/replication at both mRNA and protein levels. Investigations of the mechanisms revealed that TLR3 activation of iMg by poly (I:C) induced the expression of both type I and type III IFNs. Compared with untreated cells, the poly (I:C)‐treated iMg expressed significantly higher levels of IFN‐stimulated genes (ISGs) with known anti‐HIV activities (ISG15, MxB, Viperin, MxA, and OAS‐1). In addition, TLR3 activation elicited the expression of the HIV entry coreceptor CCR5 ligands (CC chemokines) in iMg. Furthermore, the transcriptional profile analysis showed that poly (I:C)‐treated cells had the upregulated IFN signaling genes (ISG15, ISG20, IFITM1, IFITM2, IFITM3, IFITM10, APOBEC3A, OAS‐2, MxA, and MxB) and the increased CC chemokine signaling genes (CCL1, CCL2, CCL3, CCL4, and CCL15). These observations indicate that TLR3 is a potential therapy target for activating the intracellular innate immunity against HIV infection/replication in human microglial cells. Therefore, further studies with animal models and clinical specimens are necessary to determine the role of TLR3 activation‐driven antiviral response in the control and elimination of HIV in infected host cells.

show abstract

Induction of OAS gene family in HIV monocyte infected patients with high and low viral load

Cited by 46 publications

References 19 publications

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

Reconnaissance of the candidate genes involved in the pathogenesis of human immunodeficiency virus and targeted by antiretroviral therapy

Activation of Toll‐like receptor 3 inhibits HIV infection of human iPSC‐derived microglia

Contact Info

Product

Resources

About