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 ...