R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

Abstract

HIV envelope binds to and signals through its primary cellular receptor, CD4, and through a coreceptor, either CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4). Here, we evaluate the response of peripheral blood mononuclear cells to a panel of genetically diverse R5 and X4 envelope proteins. Modulation of gene expression was evaluated by using oligonucleotide microarrays. Activation of transcription factors was evaluated by using an array of oligonucleotides encoding transcription factor binding sites. Responses were strongly influenced by coreceptor specificity. Treatment of cells from CCR5⌬32 homozygous donors with glycoprotein (gp)120 derived from an R5 virus demonstrated that the majority of responses elicited by R5 envelopes required engagement of CCR5. R5 envelopes, to a greater extent than X4 envelopes, induced the expression of genes belonging to mitogenactivated protein kinase signal transduction pathways and genes regulating the cell cycle. A number of genes induced by R5, but not X4, envelopes were also up-regulated in the resting CD4 ؉ T cell population of HIV-infected individuals. These results suggest that R5 envelope facilitates replication of HIV in the pool of resting CD4 ؉ T cells. Additionally, signaling by R5 gp120 may facilitate the transmission of R5 viruses by inducing a permissive environment for HIV replication.ϩ T cells begins with the fusion of the viral envelope with the outer membrane of a target cell. Fusion is initiated when the viral envelope glycoprotein (gp)120 binds first to CD4 and then to a coreceptor, primarily CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4) (1-4). These interactions between gp120 and cell-surface receptors transduce signals in the target cell. Ligation of CD4 by gp120 increases the tyrosine kinase activity of p56lck, a src-related protein kinase associated with the cytoplasmic domain of CD4 on CD4 ϩ T cell membranes (5). Engagement of CCR5 and CXCR4 by gp120 also mediates signaling events (6-9), as evidenced by the rapid mobilization of Ca ϩϩ , and the phosphorylation of intracellular substrates including PYK2 and FAK (10,11). In this respect, the HIV envelope protein delivers a unique near simultaneous dual signal to CD4 ϩ T cells. No protein in the human proteome has been shown to deliver an analogous signal. The response to this stimulus depends on the state of differentiation and activation of the targeted cell. A number of reports demonstrate that envelope induces activated CD4 ϩ T cells to apoptose in vitro (12-15). Envelope proteins have also been shown to disrupt antigen-specific CD4 ϩ T cell responses (16). We have focused on the impact of envelope-mediated signaling on resting CD4 ϩ T cells. These cells constitute one of the latent reservoirs of HIV that prevents eradication of virus from infected individuals, even after prolonged treatment with potent antiretroviral drugs (17,18). In vitro exposure of resting CD4 ϩ T cells derived from HIV-infected individuals to envelope results in a burst of viral replicatio...

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