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.
Department of Pathology, Immunology, and Laboratory Medicine, Box 100275, University of Florida College of Medicine, 1600 S.W. Archer Rd., Gainesville, FL 32610, USA.
Carter R
CR
Coberley
James J
JJ
Kohler
Joseph N
JN
Brown
Joseph T
JT
Oshier
Henry V
HV
Baker
Michael P
MP
Popp
John W
JW
Sleasman
Maureen M
MM
Goodenow
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