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.
Highlights
In aging HIV-infected populations, comorbid diseases are important determinants of morbidity and mortality
Given that TGF-β signaling is upregulated by Tat, cigarette smoke and in chronic lung diseases, we tried to determine the effects of persistent TGF-β signaling on HIV infection in primary bronchial epithelium redifferentiated ex-vivo
Persistent low-level viral replication coupled with expression of viral proteins not controlled by antiretrovirals are the principal causes of non-AIDS comorbidities in people living with HIV41,42
Summary
In aging HIV-infected populations, comorbid diseases are important determinants of morbidity and mortality. HIV Tat is an immediate early gene of HIV and its expression is not suppressed by antiretrovirals[1,2,3,4] Lung diseases such as COPD, are emerging as significant comorbidities in the HIV-infected population[5,6]. TGF-β isoforms are expressed and secreted by several cell types in the airway, including epithelia in association with a latency-associated peptide This provides a TGF-β reservoir in the extracellular matrix[12] that participates in normal lung physiological processes and functions in local immunomodulation, regulation of cell proliferation and differentiation, as well as the control of normal tissue repair. TGF-β signaling is upregulated by HIV Tat, cigarette smoke and in chronic lung diseases like COPD, asthma, pulmonary fibrosis www.nature.com/scientificreports/. We have previously reported that TGF-β and cigarette smoke suppress miR-141-5p to promote CCR5 expression on primary bronchial epithelial cells, which increases viral entry and infection by R5-tropic HIV. Taken together with our earlier reports, TGF-β signaling in the airway promotes infection of bronchial epithelium and increases the reservoir pool in the airway
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