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INTRODUCTION:Over the past two decades, there has been a growing emphasis on host restriction factors. However, a comprehensive understanding of their role in modulating HIV-1 infection in vivorequires further detailed investigation. Intracellular iron levels can affect HIV-1 replication by influencing expression of host cell viral restriction factors. Systemic Lupus Erythematosus (SLE) is characterized by upregulation of interferon response and the coexistence of SLE and HIV infection is rare. In lupus nephritis, deregulation of proteins involved in iron homeostasis have also been identified, with hepcidin suggested to play a role in disease severity .Hif1α, a protein regulated by hypoxia and under iron depletion, and reported to block HIV transcription, is upregulated in SLE. High levels of IL-10 and IL-16 which inhibits HIV infection are upregulated in SLE. APOBECs and oxysterols and Interferon Regulating Factors (IRFs) are also known to be upregulated in SLE. The current study is aimed to investigate ex vivo HIV-1 infection in peripheral blood mononuclear cells (PBMCs) derived from individuals SLE and identify factors that contributed to this inhibition.

This study aims to clarify the N6-methyladenosine (m6A) modification of LINC01006, which is involved in migration, invasion and proliferation of non-small cell lung cancer (NSCLC).

Concerted action of numerous positively acting cellular factors is essential for Human immunodeficiency virus type 1 (HIV-1) replication but in turn is challenged by anti-viral restriction factors. Previously we showed that ex vivo one round HIV-1 replication and replication of fully competent T-tropic HIV-1(IIIB) is significantly reduced in peripheral blood mononuclear cells (PBMCs) obtained from patients with Sickle Cell Disease (SCD). Further, we identified and confirmed CDKN1A (p21) and CH25H as host restriction factors expressed in SCD PBMCs that may contribute to the HIV-1 inhibition, in addition to the previously reported SAMHD1 and IKBα. Since CH25H is an interferon stimulated gene (ISG), we analyzed IRFs and interferon expression in SCD PBMCs. Higher levels of IRF7 and IFNβ mRNA were observed in SCD PBMCs compared to controls. We probed further to ascertain if hemin or sickle Hb was responsible for interferon response. We found upregulation of IFNβ in THP-1 - derived macrophages treated with lysates of HbSS RBCs or purified HbS as compared to untreated or HbA treated controls. HbSS RBCs lysates and purified HbS inhibited HIV-1 gagmRNA expression in monocyte-derived macrophages infected with HIV-1(Ba-L). Recent clinical study showed increased levels of CD4 in HIV-1 infected SCD patients in Africa. Thus we analyzed CD4 levels in HIV-1 IIIB infected SCD PBMCs, and found them to be higher compared to controls. Levels of HIV-1 nefmRNA, that controls CD4 expression was lower in HIV-1 IIIB infected SCD PBMCs. As Nef counteracts SERINC3/5 restriction factor, we analyzed its expression as well as the expression of AP2 clathrin adaptor that is required for Nef mediated internalization of CD4. AP2 expression was lower and SERINC5 expression was higher in SCD PBMCs.

Human immunodeficiency virus type 1 (HIV-1) is challenged by intrinsic antiviral restriction factors which are counteracted with its own viral proteins. We recently showed that in Sickle Cell Disease (SCD), anti-viral restriction factor SAMHD1 is activated and inhibits ex vivo HIV-1 infection. Activation of SAMHD1 is caused by a reduced phosphorylation by CDK2, that are inhibited by reduced levels of intracellular iron as found in SCD peripheral blood mononuclear cells (PBMCs). The present study was aimed at identifying additional HIV-1 restriction factors in SCD PBMCs. We used a customized array that included 43 known anti-HIV-1 restriction factors to measure mRNA expression of anti-viral factors. The identified factors were further validated with shRNA-mediated knockdowns of the identified genes and their effect on HIV-1 replication in cultured and primary cells.We also mimicked SCD conditions by treating PBMCs from healthy donors with hemin and iron chelators. We observed anupregulation of 19 genes in SCD PBMCs including APOBEC3A, APOBEC3C, TRIM5α, TRIM22, MX2 and RSAD2 which were significantly upregulated and were further validated using real-time q-PCR. In PBMCs treated with hemin, APOBEC3A, RASD2 and MX2 mRNAs were found to be overexpressed, whereas TRIM5α expression was increased in PBMC treated with either hemin or iron chelators. Knockdowns by shRNA of APOBEC3C and TRIM5α, but not APOBEC3A or TRIM22 induced HIV-1 replication. In conclusion, APOBEC3A, APOBEC3C, TRIM5α, TRIM22, MX2 and RSAD2 may also contribute to HIV-1 restriction in SCD. Similar to SAMHD1, these factors are likely to be modulated by hemolysis and intracellular iron levels. Our findings further point to the contribution of hemolysis and deregulated iron metabolism to potential HIV-1 restriction in SCD.