Impact on genetic networks in human macrophages by a CCR5 strain of human immunodeficiency virus type 1.
Human immunodeficiency virus type 1 (HIV-1) impacts multiple lineages of hematopoietic cells, including lymphocytes and macrophages, either by direct infection or indirectly by perturbations of cell networks, leading to generalized immune deficiency. We designed a study to discover, in primary human macrophages, sentinel genetic targets that are impacted during replication over the course of 7 days by a CCR5-using virus. Expression of mRNA and proteins in virus- or mock-treated macrophages from multiple donors was evaluated. Hierarchical agglomerative cluster analysis grouped into distinct temporal expression patterns >900 known human genes that were induced or repressed at least fourfold by virus. Expression of more than one-third of the genes was induced rapidly by day 2 of infection, while other genes were induced at intermediate (day 4) or late (day 7) time points. More than 200 genes were expressed exclusively in either virus- or mock-treated macrophage cultures, independent of the donor, providing an unequivocal basis to distinguish an effect by virus. HIV-1 altered levels of mRNA and/or protein for diverse cellular programs in macrophages, including multiple genes that can contribute to a transition in the cell cycle from G(1) to G(2)/M, in contrast to expression in mock-treated macrophages of genes that maintain G(0)/G(1). Virus treatment activated mediators of cell cycling, including PP2A, which is impacted by Vpr, as well as GADD45 and BRCA1, potentially novel targets for HIV-1. The results identify interrelated programs conducive to optimal HIV-1 replication and expression of genes that can contribute to macrophage dysfunction.
Coberley
Carter R
CR
Department of Pathology, Immunology, and Laboratory Medicine, Box 100275, University of Florida College of Medicine, 1600 S.W. Archer Rd., Gainesville, FL 32610, USA.
Kohler
James J
JJ
Brown
Joseph N
JN
Oshier
Joseph T
JT
Baker
Henry V
HV
Popp
Michael P
MP
Sleasman
John W
JW
Goodenow
Maureen M
MM
D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D019713:Receptors, CCR5 / Q000502:physiology*; D014779:Virus Replication
D019713:Receptors, CCR5; D016203:CDC2 Protein Kinase