title: Signaling through the lymphotoxin-beta receptor stimulates HIV-1 replication alone and in cooperation with soluble or membrane-bound TNF-alpha.
abstract: The level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis. Among host immune factors, the cytokine TNF-alpha has previously been shown to increase HIV-1 replication in various monocyte and T cell model systems. Here, we demonstrate that signaling through the TNF receptor family member, the lymphotoxin-beta (LT-beta) receptor (LT-betaR), also regulates HIV-1 replication. Furthermore, HIV-1 replication is cooperatively stimulated when the distinct LT-betaR and TNF receptor systems are simultaneously engaged by their specific ligands. Moreover, in a physiological coculture cellular assay system, we show that membrane-bound TNF-alpha and LT-alpha1beta2 act virtually identically to their soluble forms in the regulation of HIV-1 replication. Thus, cosignaling via the LT-beta and TNF-alpha receptors is probably involved in the modulation of HIV-1 replication and the subsequent determination of HIV-1 viral burden in monocytes. Intriguingly, surface expression of LT-alpha1beta2 is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-alpha1beta2 expression, and HIV-1 replication. Given the critical role that LT-alpha1beta2 plays in lymphoid architecture, we speculate that LT-alpha1beta2 may be involved in HIV-associated abnormalities of the lymphoid organs.
authors.affiliation: Center for Blood Research and Division of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Marshall
authors.forename: B M
authors.initials: BM
authors.lastname: Brinkman
authors.forename: C M
authors.initials: CM
authors.lastname: Ambrose
authors.forename: P A
authors.initials: PA
authors.lastname: Pesavento
authors.forename: A M
authors.initials: AM
authors.lastname: Uglialoro
authors.forename: E
authors.initials: E
authors.lastname: Teng
authors.forename: R W
authors.initials: RW
authors.lastname: Finberg
authors.forename: J L
authors.initials: JL
authors.lastname: Browning
authors.forename: A E
authors.initials: AE
authors.lastname: Goldfeld
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D004357:Drug Synergism; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha