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Replication in Lymphatic Tissue Host Genes

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Replication in Lymphatic Tissue Host Genes Host Genes Associated with HIV-1 Replication in Lymphatic Tissue Anthony J. Smith, Qingsheng Li, Stephen W. Wietgrefe, Timothy W. Schacker, Cavan S. Reilly and Ashley T. Haase This information is current as of September 25, 2021. J Immunol published online 8 October 2010 http://www.jimmunol.org/content/early/2010/10/08/jimmun ol.1002197 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/10/08/jimmunol.100219 Material 7.DC1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 8, 2010, doi:10.4049/jimmunol.1002197 The Journal of Immunology Host Genes Associated with HIV-1 Replication in Lymphatic Tissue Anthony J. Smith,* Qingsheng Li,*,1 Stephen W. Wietgrefe,* Timothy W. Schacker,† Cavan S. Reilly,‡ and Ashley T. Haase* Much effort has been spent recently in identifying host factors required for HIV-1 to effectively replicate in cultured human cells. However, much less is known about the genetic factors in vivo that impact viral replication in lymphatic tissue, the primary an- atomical site of virus–host interactions where the bulk of viral replication and pathogenesis occurs. To identify genetic determi- nants in lymphatic tissue that critically affect HIV-1 replication, we used microarrays to transcriptionally profile and identify host genes expressed in inguinal lymph nodes that were associated determinants of viral load. Strikingly, ∼95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset 1) inhibit cellular activation/proliferation (e.g., TCFL5, SOCS5 and SCOS7, KLF10), 2) promote heterochromatin formation (e.g., HIC2, CREBZF, Downloaded from ZNF148/ZBP-89), 3) increase collagen synthesis (e.g., PLOD2, POSTN, CRTAP), and 4) reduce cellular transcription and trans- lation. Potential anti–HIV-1 restriction factors were also identified (e.g., NR3C1, HNRNPU, PACT). Only ∼5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all of these genes function in innate and adaptive immunity, particularly highlighting heightened gene expression in the IFN system. We conclude that this conventional host response cannot contain HIV-1 replication and, in fact, could well contribute to increased replication through immune activation. More importantly, genes that have a negative association with virus replication point to target cell availability and potentially new http://www.jimmunol.org/ viral restriction factors as principal determinants of viral load. The Journal of Immunology, 2010, 185: 000–000. ver the last decade, systems biology has taken on an licates in the complex environment of lymphatic tissue (LT) in increasingly important role in investigating microbial dis- the context of a host responding to infection. In previous micro- O eases, delineating salient features of the host-pathogen array studies of HIV-1 infection in LT, we have shown that infection relationship, and identifying potential host genes that are critical massively perturbs host gene expression and that this transcrip- determinants of microbial replication and pathogenesis. In the case tional profile is highly dependent on stage of disease (9). In this of HIV-1, which like any obligate intracellular pathogen relies on work, we report studies that go beyond this initial identification of the transcriptional and translational machinery of the host cell to stage-specific features of the host response in LT to now identify by guest on September 25, 2021 complete its life cycle (1–3), these studies have revealed com- genes that play important roles in viral replication in vivo. We now ponents of host gene expression that establish a favorable intra- show the following: 1) there is little overlap between genes in vivo cellular environment for efficient virus replication. For example, compared with genes in vitro that correlate with viral replication; genomics-based approaches have, to date, documented changes in 2) paradoxically, host immune responses correlate with high viral gene expression in cultured cells during HIV-1 infection (4), and loads; and 3) ∼95% of the correlations are inverse correlations that more recently, small interfering RNA technology has identified point to the importance of target cell availability, cellular activa- hundreds of host genes seemingly indispensable for HIV-1 repli- tion, transcriptional factors, and new inhibitors as determinants of cation in vitro (5–8). viral load in vivo. In contrast, much less is known about host genes that play important roles in viral replication in vivo in which HIV-1 rep- Materials and Methods Ethics statement This study was conducted according to the principles expressed in the *Department of Microbiology, †Department of Medicine, Medical School, and ‡Division of Biostatistics, School of Public Health, University of Minnesota, Minne- Declaration of Helsinki. This study was approved by the Institutional apolis, MN 55455 Review Board of the University of Minnesota. All patients provided written informed consent for the collection of samples and subsequent analysis. 1Current address: Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE. Lymph node biopsy specimens Received for publication July 2, 2010. Accepted for publication August 25, 2010. Inguinal lymph node biopsies from 22 untreated HIV-1–infected individuals This work was supported by National Institutes of Health Grant R01 AI056997 (to at different clinical stages were obtained for this University of Minnesota A.T.H.). Institutional Review Board-approved microarray study. Viral load meas- The sequences presented in this article have been submitted to the Gene Expression urements were obtained the same day as biopsies. Each lymph node biopsy Omnibus Web site under accession number GSE21589. was placed into a Falcon tube and snap frozen by dropping it into liquid Address correspondence and reprint requests to Dr. Ashley T. Haase, Department of nitrogen. Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware RNA extraction, synthesis of biotin-labeled cRNA probes, and Street S.E., Minneapolis, MN 55455. E-mail address: [email protected] microarray hybridization The online version of this article contains supplemental material. Abbreviations used in this paper: CIA, chronic immune activation; LT, lymphatic Frozen lymph nodes were homogenized with a power homogenizer (Heat tissue; PKR, dsRNA-dependent protein kinase; TReg, regulatory T. Systems Ultrasonic, Farmingdale, NY) in TRIzol (Invitrogen, Carlsbad, CA) without thawing. Total RNA was isolated, according to the manu- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 facturer’s protocol, and further purified with an RNeasy mini kit (Qiagen, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002197 2 HOST GENES IN LYMPH NODE ASSOCIATED WITH HIV-1 Valencia, CA). Double-stranded cDNA and biotin-labeled cRNA probes reagent (Biocare Medical) for 15 min at room temperature. A primary Ab were synthesized from 5 mg total RNA with a MessageAmp II aRNA kit specific for collagen type 1 (Sigma-Aldrich; clone Col-1, catalog C2456) (Ambion, Austin, TX). The cRNA probes were column purified and was diluted 1:100 in Tris-NaCl-blocking buffer (0.1 M Tris-HCl [pH 7.5]; fragmented with a fragmentation kit (Ambion). 0.15 M NaCl; 0.05% Tween 20 with DuPont [Wilmington, DE] blocking Fifteen micrograms of fragmented cRNA was hybridized to an Affy- buffer) and incubated overnight at 4˚C. After the primary Ab incubation, metrix Human Genome U133 Plus 2.0 array (Santa Clara, CA). After sections were washed with PBS and then incubated with fluorophore- hybridization, chips were washed, stained with streptavidin-PE, and conjugated secondary Abs (Alexa Fluor dyes; Invitrogen) in 5% nonfat scanned with GeneChip Operating Software at the Biomedical Genomics milk for 2 h at room temperature. These sections were washed and Center at the University of Minnesota. The experiments from each RNA mounted using Aqua Poly/Mount (Polysciences, Warrington, PA). Immu- sample were duplicated in the preparation of each cRNA probe and nofluorescent micrographs were taken using an Olympus BX61 Fluoview microarray hybridization. confocal microscope with the following objectives: 320 (0.75 NA), 340 (0.75 NA), and 360 (1.42 NA); images were acquired using Olympus Microarray data analysis Fluoview software (Melville, NY; version 1.7a). Isotype-matched IgG- or IgM-negative control Abs in all instances yielded negative staining results. The .cel files produced by the Affymetrix data analysis platform were uploaded into the Expressionist program (Genedata, Pro version 4.5, Basel, Microarray data accession number
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