Signal transduction induced by apoptotic cells inhibits HIV transcription in monocytes/macrophages.
The primary targets of HIV are CD4(+) T cells and macrophages. HIV infection is associated with an increase in apoptosis of infected and uninfected CD4(+) T cells, and these infected cells undergo apoptosis and produce HIV virions with phosphatidylserine (PS) on their surface. During phagocytosis of apoptotic cells, macrophages, using an array of receptors, are able to perceive various surface changes on apoptotic cells. The engagement of phagocytic receptors by ligands on the apoptotic cell surface results in the activation of signaling cascades, which facilitate engulfment. In this study, we examined how PS associated with virions and apoptotic cells influences HIV replication. We demonstrate that virus-associated PS is required for HIV infection of macrophages at a step prior to integration but following strong-stop, indicating that PS-initiated signals alter the establishment of HIV provirus. Conversely, apoptotic cells inhibited HIV transcription in infected macrophages, although this ability to suppress transcription was independent of PS. Furthermore, we show that ELMO, a key signaling molecule that participates in the phagocytosis of apoptotic cells, inhibited HIV transcription; however, knocking down endogenous ELMO expression in infected U937 cells rescued HIV transcription when these cells were coincubated with apoptotic targets. Taken together, these data show that apoptotic cells and the signals, which they initiate upon recognition by macrophages, influence the successful establishment of HIV infection and provirus transcription.
Gekonge
Bethsebah N
BN
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Schiralli
Gillian
G
Schlegel
Robert A
RA
Henderson
Andrew J
AJ
D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D010718:Phosphatidylserines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000276:immunology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D020298:U937 Cells; D014779:Virus Replication / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C465214:ELMO1 protein, human; C486678:ELMO2 protein, human; D010718:Phosphatidylserines; D034741:RNA, Small Interfering