Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically associated with all forms of Kaposi’s sarcoma worldwide. Little is currently known about the role of microRNAs (miRNAs) in KSHV entry. We recently demonstrated that KSHV induces a plethora of host cell miRNAs during the early stages of infection. In this study, we show the ability of host cell novel miR-36 to specifically inhibit KSHV-induced expression of interferon induced transmembrane protein 1 (IFITM1) to limit virus infection of cells. Transfecting cells with miR-36 mimic specifically lowered IFITM1 expression and thereby significantly dampening KSHV infection. In contrast, inhibition of miR-36 using miR-36 inhibitor had the direct opposite effect on KSHV infection of cells, allowing enhanced viral infection of cells. The effect of miR-36 on KSHV infection of cells was at a post-binding stage of virus entry. The highlight of this work was in deciphering a common theme in the ability of miR-36 to regulate infection of closely related DNA viruses: KSHV, Epstein-Barr virus (EBV), and herpes simplexvirus-2 (HSV-2). Taken together, we report for the first time the ability of host cell miRNA to regulate internalization of KSHV, EBV, and HSV-2 in hematopoietic and endothelial cells.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma (KS)[1]
Expression of miR-36 gradually increased from 5 min post infection (PI) and peaked at 30 min PI in KSHV infected BJAB (Fig. 1A) and HMVEC-d cells (Fig. 1B)
Since miRNAs discovery over 20 years ago, miRNAs have been established as key players in the molecular mechanisms of mammalian biology including the maintenance of normal homeostasis and the regulation of disease pathogenesis
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma (KS)[1]. To a lesser extent, KSHV is etiologically associated with rare neoplastic disorders like primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD)[2]. KSHV, human immunodeficiency virus 1 (HIV-1), Epstein-Barr virus (EBV), and herpes simplex virus type 1 (HSV-1) are few examples of the limited number of viruses that encode their own miRNAs14,15. There is limited work along the lines of understanding the effects of cellular miRNAs in response to early stages of KSHV infection of cells; internalization of the virus. The effect of IFITM1 on the closely related virus, Epstein-Barr virus (EBV) and a distant relative, herpes simplex virus-2 (HSV-2) followed the same pattern as in KSHV. These results reveal a layer of common theme in the regulation of host cell genes by miRNAs in the internalization of KSHV and related viruses
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