TGF-β1 increases viral burden and promotes HIV-1 latency in primary differentiated human bronchial epithelial cells

Abstract

Combination antiretroviral therapy (cART) has increased the life expectancy of HIV patients. However, the incidence of non-AIDS associated lung comorbidities, such as COPD and asthma, and that of opportunistic lung infections have become more common among this population. HIV proteins secreted by the anatomical HIV reservoirs can have both autocrine and paracrine effects contributing to the HIV-associated comorbidities. HIV has been recovered from cell-free bronchoalveolar lavage fluid, alveolar macrophages, and intrapulmonary lymphocytes. We have recently shown that ex - vivo cultured primary bronchial epithelial cells and the bronchial brushings from human subjects express canonical HIV receptors CD4, CCR5 and CXCR4 and can be infected with HIV. Together these studies suggest that the lung tissue can serve as an important reservoir for HIV. In this report, we show that TGF-β1 promotes HIV latency by upregulating a transcriptional repressor BLIMP-1. Furthermore, we identify miR-9-5p as an important intermediate in TGF-β-mediated BLIMP-1 upregulation and consequent HIV latency. The transcriptionally suppressed HIV can be reactivated by common latency reactivating agents. Together our data suggest that in patients with chronic airway diseases, TGF-β can elevate the HIV viral reservoir load that could further exacerbate the HIV associated lung comorbidities.

The Prediction of miRNAs in SARS-CoV-2 Genomes: hsa-miR Databases Identify 7 Key miRs Linked to Host Responses and Virus Pathogenicity-Related KEGG Pathways Significant for Comorbidities

“…"Glycosaminoglycan biosynthesis-heparan sulfate/heparin" was here related to miRs 3934-3. Heparan sulfate proteoglycans have previously been identified to provide the binding sites for SARS-CoV-2 invasion at the early attachment phase [76]. Furthermore, human coronavirus NL63 has been shown to utilise heparan sulfate proteoglycans for target cell attachment [77].…”

Aberrant MicroRNAomics in Pulmonary Complications: Implications in Lung Health and Diseases

“…Tobacco smoking is the principal risk factor for COPD. Cigarette smokers and COPD patients demonstrate chronic induction of TGF-β signaling 98, 99, 100, 101, 102. We have demonstrated that TGF-β upregulates miR-145-5p in bronchial epithelial cells 100 .…”

MicroRNAs for Virus Pathogenicity and Host Responses, Identified in SARS-CoV-2 Genomes, May Play Roles in Viral-Host Co-Evolution in Putative Zoonotic Host Species

“…miR-5197 is also related to the KEGG morphine addiction pathway, which is linked to enhanced HIV-1 infection, HCV replicon expression, the reduced clearance of pulmonary influenza virus infection in rats, and increased SAIDS in rhesus monkeys [ 52 , 53 , 54 , 55 , 56 , 57 ]. miR-5197 furthermore influences the metabolism of xenobiotics by cytochrome P450 mechanisms and the TGF-β signaling pathway, which is associated with viral entry and HIV infection [ 58 ] and is strongly linked to both pulmonary and cardiovascular diseases [ 59 , 60 , 61 ]. Furthermore, miR-5197 is related to p53 regulatory pathways and cancers, ubiquitin-related proteolysis, and molecular and cellular GO pathways linked to nucleic acid binding and to nuclear and organelle function ( Figure S2 ) (please see further in depth discussion on these pathways in Ref.…”