Cell adhesion through alphaV-containing integrins is required for efficient HIV-1 infection in macrophages.
Monocytes and macrophages are an important reservoir of human immunodeficiency virus (HIV) and may represent the largest reservoir of this virus in tissues. Differentiation of monocytes into macrophages leads to cell attachment and susceptibility to infection and replication of HIV. Among other cell-surface molecules, integrins are overexpressed during monocyte-macrophage differentiation and may play a role in the replication cycle of envelope viruses including HIV. Here, we show that inhibition of alphaV integrin in monocyte-derived macrophages, by RNA interference or their inhibition by a selective small heterocyclic RGD-mimetic nonpeptide compound, inhibited the replication of HIV in the absence of cytotoxicity. Interference or inhibition of alphaV integrins triggered a signal transduction pathway, leading to down-regulation of nuclear factor-kappaB-dependent HIV-1 transcription. Such inhibition was mediated by a MAP-kinase signaling cascade, probably involving ERK1/2, p38-mitogen-activated protein kinases, and HSP27. In conclusion, our results reveal a significant role of integrin alphaV-mediated adhesion in HIV-1 infection of macrophages.
Ballana
Ester
E
Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Pauls
Eduardo
E
Senserrich
Jordi
J
Clotet
Bonaventura
B
Perron-Sierra
Françoise
F
Tucker
Gordon C
GC
Esté
José A
JA
D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D039564:Integrin alphaV; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases