Impact on genetic networks in human macrophages by a CCR5 strain of human immunodeficiency virus type 1.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Coberley, CR; Kohler, JJ; Brown, JN; Oshier, JT; Baker, HV; Popp, MP; Sleasman, JW; Goodenow, MM

Published Date

  • November 2004

Published In

Volume / Issue

  • 78 / 21

Start / End Page

  • 11477 - 11486

PubMed ID

  • 15479790

Pubmed Central ID

  • 15479790

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/JVI.78.21.11477-11486.2004

Language

  • eng

Conference Location

  • United States