title: Mycobacterial phosphatidylinositol mannoside 6 (PIM6) up-regulates TCR-triggered HIV-1 replication in CD4+ T cells.
abstract: Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficiency virus (HIV-1) worldwide. HIV-1 load and heterogeneity are increased both locally and systemically in active TB. Mycobacterium tuberculosis (MTB) infection supports HIV-1 replication through dysregulation of host cytokines, chemokines, and their receptors. However the possibility that mycobacterial molecules released from MTB infected macrophages directly interact with CD4(+) T cells triggering HIV-1 replication has not been fully explored. We studied the direct effect of different MTB molecules on HIV-1 replication (R5-tropic strain Bal) in anti-CD3- stimulated CD4(+) T cells from healthy donors in an antigen presenting cell (APC)-free system. PIM6, a major glycolipid of the mycobacterial cell wall, induced significant increases in the percent of HIV-1 infected T cells and the viral production in culture supernatants. In spite of structural relatedness, none of the other three major MTB cell wall glycolipids had significant impact on HIV-1 replication in T cells. Increased levels of IFN-γ in culture supernatants from cells treated with PIM6 indicate that HIV-1 replication is likely dependent on enhanced T cell activation. In HEK293 cells transfected with TLR2, PIM6 was the strongest TLR2 agonist among the cell wall associated glycolipids tested. PIM6 increased the percentage of HIV infected cells and viral particles in the supernatant in a T-cell-based reporter cell line (JLTRg-R5) transfected with TLR1 and TLR2 but not in the cells transfected with the empty vector (which lack TLR2 expression) confirming that PIM6-induced HIV-1 replication depends at least partially on TLR2 signaling.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Myriam E
authors.initials: ME
authors.lastname: Rodriguez
authors.forename: Candace M
authors.initials: CM
authors.lastname: Loyd
authors.forename: Xuedong
authors.initials: X
authors.lastname: Ding
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Karim
authors.forename: David J
authors.initials: DJ
authors.lastname: McDonald
authors.forename: David H
authors.initials: DH
authors.lastname: Canaday
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Rojas
mesh_terms: D000942:Antigens, Bacterial / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C034154:phosphatidylinositol mannoside