Reciprocal Interactions between Human T-Lymphotropic Virus Type 1 and Prostaglandins: Implications for Viral Transmission

Abstract

Human T-lymphotropic virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia/lymphoma, is transmitted through breast milk and seminal fluid, which are rich in prostaglandins (PGs). We demonstrate that PGE 2 upregulates the HTLV-1 long terminal repeat promoter through the protein kinase A pathway, induces replication of HTLV-1 in peripheral blood mononuclear cells (PBMC) derived from asymptomatic carriers, and enhances transmission of HTLV-1 to cord blood mononuclear cells (CBMC). Furthermore, HTLV-1 Tax transactivates a promoter for cyclooxygenase 2, a PG synthetase, and induces PGE 2 expression in PBMC or CBMC. Thus, HTLV-1 interacts with and benefits from PGs, constituents of its own vehicle for transmission.Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma and is transmitted horizontally or vertically through blood, seminal fluid, or breast milk (reviewed in references 13 and 37).Prostaglandins (PGs) are synthesized and secreted by most human tissues and cell types; however, they are especially abundant in seminal fluid and breast milk (2, 7, 9, 10). PGs, particularly those of the E series, are widely regarded as pleiotropic immunomodulatory molecules, and regulation of their expression appears to be critical for a number of immune responses (reviewed in references 26 and 29). There are two isoforms of cyclooxygenase (COX) that catalyze the formation of PGs from arachidonic acid. While COX-1 is a housekeeping gene that is expressed constitutively, COX-2 is an immediateearly response gene that is highly inducible by mitogenic and inflammatory stimuli and is considered essential for the induction of the aforementioned immune responses (reviewed in reference 32).In this study we demonstrate that (i) PGE 2 upregulates the HTLV-1 long terminal repeat (LTR) promoter through the protein kinase A (PKA) pathway, induces viral replication in peripheral blood mononuclear cells (PBMC) derived from asymptomatic HTLV-1 carriers, and enhances transmission of HTLV-1 to cord blood mononuclear cells (CBMC) and that (ii) HTLV-1 Tax transactivates a COX-2 promoter and induces PGE 2 production in PBMC. These data suggest that HTLV-1 interacts with and benefits from PGs that are abundant in seminal fluid and breast milk, vehicles for virus transmission. MATERIALS AND METHODSReagents. PGE 2 , H7, HA-1004, mitomycin C (MMC), 3Ј-azido-3Ј-deoxythymidine (AZT), phorbol 12-myristate 13-acetate (PMA), and ionomycin were purchased from Sigma (St. Louis, Mo.). MMC treatment of cells was performed as described previously (1).Infectious HTLV-1 stock which was rendered devoid of cell culture supernatants by directly pelleting virions was obtained from Advanced Biotechnologies, Inc. (Columbia, Md.). Glutathione S-transferase (GST) and GST-Tax protein were propagated as described previously (23).Plasmids and transient-expression assays. pU3R-luc, a generous gift of K.-T. Jeang (National Institute of Allergy and Infectious Diseases [NIAID], Bethesda, Md.), carries the luciferase gene ...

Cyclooxygenase 2 Induced by Kaposi's Sarcoma-Associated Herpesvirus Early during In Vitro Infection of Target Cells Plays a Role in the Maintenance of Latent Viral Gene Expression

“…Incubation of HFF cells with 2 g/ml of gB for 30 min or 8 h induced the COX-2 levels by 2 , which is the most abundant lipid mediator produced in response to cytokines and mitogens and mediates many symptoms of inflammation (53,74). Previous studies have shown that infection by several viruses leads to PGE 2 release by the infected cells (6,23,27,43,86). PGE 2 biosynthesis has been shown to be dysregulated in a variety of neoplasms, and KS is classified as a chronic-inflammation-associated malignancy.…”

“…These include herpesviruses such as HSV (9), HCMV (86), pseudorabies virus (52), HHV-6 (27), EBV (45), and MHV-68 (71), as well as other viruses such as hepatitis B virus (15,35) and human T-cell leukemia virus type 1 (HTLV-1) (42,43,45). In addition, rhesus cytomegalovirus even encodes a COX-2 homolog in its genome, thus emphasizing the importance of this enzyme in viral infections.…”

Activation of Monocyte Cyclooxygenase-2 Gene Expression by Human Herpesvirus 6

“…PGE 2 , an arachidonic acid metabolite, influences several inflammatory processes such as cytokine production, antibody formation, phagocytosis, and cell multiplication. PGE 2 production has been observed following infection with several pathogens including viruses such as HSV-1, human cytomegalovirus (HCMV), HIV-1, and HTLV-1 (26,27,29,94). It is worth noting that viruses with immunosuppressive properties such as CMV and HIV have been reported to induce PGE 2 from monocytes, an event directly linked to impaired T cell proliferation (26,27).…”

Sexual transmission of human T-cell lymphotropic virus type 1

“…They subsequently found that the virus interacted with and benefi tted from PGs as follows: prostaglandin E2 (PGE2) enhanced HTLV-1 replication by upregulating the HTLV-1 long terminal repeat (LTR) promoter, and HTLV-1 Tax transactivated a promoter for ciclo-oxigenase-2 (COX-2), a PG synthetase, which stimulated the production of PGE2. This synergistic mechanism most likely accelerates viral transmission through seminal fl uid 91 .…”