Scientific Publications by FDA Staff
J Immunol 2004 Dec 1;173(11):6735-44
Mechanisms for Macrophage-Mediated HIV-1 Induction.
Devadas K, Hardegen NJ, Wahl LM, Hewlett IK, Clouse KA, Yamada KM, Dhawan S
Devadas K, US FDA, Immunopatholgenesis Sect, Mol Virol Lab, Ctr Biol Evaluat & Res, 1401 Rockville Pike HFM-315, Rockville, MD 20852 USA US FDA, Immunopatholgenesis Sect, Mol Virol Lab, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA Natl Inst Dent & Craniofacial Res, Cellular Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA Natl Inst Dent & Craniofacial Res, Dev Mech Sect, Cranofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA
Viral latency is a long-term pathogenic condition in patients infected with HIV-1. Low but sustained virus replication in chronically infected cells can be activated by stimulation with proinflammatory cytokines such as TNF-alpha, IL-1 beta, or other host factors. However, the precise mechanism by which cellular activation induces latently infected cells to produce virions has remained unclear. In the present report, we present evidence that activation of HIV-1 replication in latently infected U1 or ACH2 cells by human macrophages is mediated by a rapid nuclear localization of NF-kappaB p50/p65 dimer with concomitant increased expression of proinflammatory cytokines. Multiplexed RT-PCR amplification of mRNA isolated from cocultures of macrophages and U1 and ACH2 cells showed significant induction of IL-1beta, IL-6, IL-8, TNF-alpha, and TGF-beta expression within 3 h of coincubation. Fixation of macrophages, U-1, or ACH2 cells with paraformaldehyde before coculture completely abrogated the induction of NF-kappaB subunits and HIV-1 replication, suggesting that cooperative interaction between the two cell types is an essential process for cellular activation. Pretreatment of macrophage-U1 or macrophage-ACH2 cocultures with neutralizing anti-TNF-alpha Ab down-regulated the replication of HIV-1. In addition, pretreatment of macrophage-U1 or macrophage-ACH2 cocultures with the NF-kappaB inhibitor (E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7082) prevented the induction of cytokine expression, indicating a pivotal role of NF-kappaB-mediated signaling in the reactivation of HIV-1 in latently infected cells by macrophages. These results provide a mechanism by which macrophages induce HIV-1 replication in latently infected cells.
|Category: Journal Article, Peer|
|PubMed ID: #15557166|
|Includes FDA Authors from Scientific Area(s): Biologics, Drugs|
|Entry Created: 2011-10-04||Entry Last Modified: 2012-08-29|