Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis.
Chemokines and cytokines play a critical role in HIV infection, serving both to modulate virus replication and to recruit target cells to the site of infection. Platelet-derived growth factor (PDGF), a mitogen and chemoattractant for a wide variety of cells, is secreted by macrophages. Since macrophages are the target cells for lentiviral infection in the brain and PDGF is a known inducer of macrophage chemoattractant protein-1 (MCP)-1, a potent chemokine closely associated with HIV encephalitis, we investigated the association of PDGF-B chain (PDGF-B) with encephalitis in macaques caused by simian human immunodeficiency virus (SHIV), a chimera of HIV and SIV. Northern blot analysis confirmed elevated expression of PDGF-B chain mRNA in the brains from encephalitic macaques. Validation of these in vivo studies was confirmed in rhesus macrophage cultures infected with SHIV(KU2) in which we demonstrated heightened expression of PDGF-B chain mRNA. Nuclear run-off analysis established transcriptional up-regulation of PDGF-B chain in virus-inoculated macrophage cultures. Reciprocally, addition of exogenous PDGF enhanced virus replication and MCP-1 expression in these cells. Inhibition of virus replication by tyrosine kinase inhibitor, STI-571, and by PDGF-B antisense oligonucleotides confirmed the specificity of the PDGF effect. Relevance of these findings was confirmed by analysis of archival brain tissue from SHIV encephalitic and non-encephalitic macaques for PDGF-B chain expression. PDGF-B chain protein expression was observed in the virus-infected cells in microglial nodules in the brains of SHIV-encephalitic macaques.
Department of Microbiology, Immunology, and Molecular Genetics, Marion Merrell Dow Laboratory of Viral Pathogenesis, Kansas City, Kansas, USA.
Raghava
R
Potula
Navneet
N
Dhillion
Yongjun
Y
Sui
Christopher A
CA
Zien
Keiko
K
Funa
David
D
Pinson
Matthew S
MS
Mayo
Dinesh K
DK
Singh
Opendra
O
Narayan
Shilpa
S
Buch
D000818:Animals; D001549:Benzamides; D015152:Blotting, Northern; D001921:Brain / Q000276:immunology / Q000821:virology*; D002478:Cells, Cultured; D054407:Chemokine CCL4; D004279:DNA, Viral / Q000235:genetics; D018792:Encephalitis, Viral / Q000209:etiology / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D000068877:Imatinib Mesylate; D008253:Macaca mulatta; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015301:Retroviruses, Simian / Q000472:pathogenicity*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D014158:Transcription, Genetic; D015854:Up-Regulation; D014779:Virus Replication
D001549:Benzamides; D054407:Chemokine CCL4; D004279:DNA, Viral; D019402:Macrophage Inflammatory Proteins; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000068877:Imatinib Mesylate