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. 2006 Mar 7;103(10):3746-51.
doi: 10.1073/pnas.0511237103. Epub 2006 Feb 27.

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

Claudia Cicala  1 , James Arthos, Elena Martinelli, Nina Censoplano, Catherine C Cruz, Eva Chung, Sara M Selig, Donald Van Ryk, Jun Yang, Shyla Jagannatha, Tae Wook Chun, Ping Ren, Richard A Lempicki, Anthony S Fauci
Affiliations

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

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

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 CCR5delta32 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 mitogen-activated 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.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Modulation of gene expression in response to treatment with genetically diverse R5 and X4 envelope proteins. Freshly isolated PBMCs from seven donors were treated with three R5 envelopes [92MW959 (M) (subgroup C), 92TH14–12 (T) (subgroup B), and JR-FL (J) (subgroup B)] and two X4 gp120s [92UG021–9 (U) (subgroup A) and NL4–3 (N) (subgroup B)] at three time points (1, 5, and 16 h). Statistical significance (t score) is reported relative to mock-treated PBMCs (red, t score >2; black, t score = 0; green, t score <−2). Hierarchical clustering analysis was used to cluster samples, and K-means clustering was used to group genes. A Venn diagram comparing overlap of the gene induced by R5 gp120s and X4 gp120s is included.
Fig. 2.
Fig. 2.
Genes induced by R5 gp120s in wild-type PBMCs are not induced in CCR5Δ32 PBMCs. The effect of R5 gp120 on those genes up-regulated by R5 gp120s in wild-type PBMCs (from Fig. 1, cluster 1) in PBMCs from CCR5Δ32 homozygous donors. R5 and X4 gp120 proteins were used to stimulate cells, and gene expression was determined at three time points (1, 5, and 16 h). Statistical significance (t score) is reported relative to mock-treated wild-type PBMCs (red, t score >2; black, t score = 0; green, t score <−2).
Fig. 3.
Fig. 3.
Transcription factor/DNA probe-binding array. Immobilized DNA probes encoding ≈90 transcription factor binding sites (represented in duplicate) were probed with nuclear extracts from freshly isolated PBMCs treated with R5 and X4 gp120s. Mock-treated nuclear lysates were included for reference. Transcription factors whose binding activity was modulated in envelope-treated cells are highlighted in boxes. Red boxes, increased DNA binding activity; green boxes, decreased DNA binding activity; black boxes, corresponding transcription factors in the mock-treated control sample are included for reference. Transcription factors discussed in the text are labeled. Results shown are representative of two separate experiments.
Fig. 4.
Fig. 4.
MAPK signaling pathway genes are induced to a greater extent by R5 envelopes than by X4 envelopes. The aggregate number of genes in each of the three main MAPK signaling pathways [p38, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), and ERK/MAPK] that were modulated by R5 and X4 envelopes are shown. See Table 2 for additional information.
Fig. 5.
Fig. 5.
Cell cycle-related genes are modulated to a greater extent by R5 gp120s than by X4 gp120s. The stages of the cell cycle where these genes are involved are indicated. Genes induced by R5 envelopes are listed in bold, and genes induced by X4 envelopes are boxed and listed in italics.
Fig. 6.
Fig. 6.
Genes up-regulated in vivo in resting CD4+ T cells of viremic individuals have significant overlap with the genes induced by R5 gp120s in vitro (cluster 1). A heat map of genes up-regulated in resting CD4+ T cells from HIV-infected viremic individuals (from ref. 29) are presented along with the heat map of genes induced in vitro by R5 gp120s (from Fig. 1, cluster 1). A Venn diagram indicating the extent of gene overlap between the two data sets is included. A Fisher exact test and an EASE score representing the probability that this overlap occurred by chance are provided. See Table 3 for additional information.
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References

    1. Alkhatib G., Broder C. C., Berger E. A. J. Virol. 1996;70:5487–5494. - PMC - PubMed
    1. Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M., et al. Nature. 1996;381:661–666. - PubMed
    1. Dragic T., Litwin V., Allaway G. P., Martin S. R., Huang Y., Nagashima K. A., Cayanan C., Maddon P. J., Koup R. A., Moore J. P., Paxton W. A. Nature. 1996;381:667–673. - PubMed
    1. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. Science. 1996;272:872–877. - PubMed
    1. Juszczak R. J., Turchin H., Truneh A., Culp J., Kassis S. J. Biol. Chem. 1991;266:11176–11183. - PubMed

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