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, 99 (14), 9380-5

HIV Envelope Induces a Cascade of Cell Signals in Non-Proliferating Target Cells That Favor Virus Replication

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HIV Envelope Induces a Cascade of Cell Signals in Non-Proliferating Target Cells That Favor Virus Replication

Claudia Cicala et al. Proc Natl Acad Sci U S A.

Abstract

Certain HIV-encoded proteins modify host-cell gene expression in a manner that facilitates viral replication. These activities may contribute to low-level viral replication in nonproliferating cells. Through the use of oligonucleotide microarrays and high-throughput Western blotting we demonstrate that one of these proteins, gp120, induces the expression of cytokines, chemokines, kinases, and transcription factors associated with antigen-specific T cell activation in the absence of cellular proliferation. Examination of transcriptional changes induced by gp120 in freshly isolated peripheral blood mononuclear cells and monocyte-derived-macrophages reveals a broad and complex transcriptional program conducive to productive infection with HIV. Observations include the induction of nuclear factor of activated T cells, components of the RNA polymerase II complex including TFII D, proteins localized to the plasma membrane, including several syntaxins, and members of the Rho protein family, including Cdc 42. These observations provide evidence that envelope-mediated signaling contributes to the productive infection of HIV in suboptimally activated T cells.

Figures

Figure 1
Figure 1
Induction of genes in response to gp120 treatment. A list of genes, which were determined by sam to be significantly modulated in response to JR-FL gp120, was generated. A subset of that list that includes those genes most up-regulated is listed by time point for PBMCs (a) and MDMs (b). Responses were also evaluated by sam independent of time, and a subset of those genes that were most up-regulated is reported in the list termed “all time points.” Accession number and definition are included for each gene. avg FC, the fold change relative to PBMCs or MDMs treated with a mock protein preparation. Genes are ranked by descending fold change. Results represent the average of four donors in PBMCs or three donors in MDMs.
Figure 2
Figure 2
Western blot analysis of gp120-treated PBMCs. Freshly isolated PBMCs were treated with JR-FL gp120 for 1, 5, or 16 h. Lysates were analyzed by Western blot analysis with a collection of ≈800 mAbs or sera (www.translab.com/TOC.shtml). Selected results are displayed.
Figure 3
Figure 3
Hierarchical cluster analysis of the genes included in the category “Cytokine/Chemokine” that are induced by gp120. Genes included in this that were significantly differentially expressed in macrophages (three donors; Mφ) or PBMCs (four donors) following treatment with gp120 were clustered (spotfire software package, Spotfire Inc., Somerville, MA; hierarchical algorithm) according to t score values derived after performing 5,000 random permutations of the expression data by using a paired test comparing treated versus untreated samples (sam software package). Changes in gene expression relative to untreated PBMCs and MDMs are indicated by a color scale in which the color red indicates up-regulation of transcription and green indicates down-regulation. Changes in gene expression for three different time points in both MDMs and PBMCs are represented.

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