Dataset Information

Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques.

ABSTRACT:

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Depletion of CD4(+) central memory T (TCM) cells dictates the tempo of progression to AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) both in the natural history of infection and in the context of vaccination. CD4(+) TCM cells of sooty mangabeys (SMs), a natural host for SIV in which infection is nonpathogenic, are less susceptible to SIV infection than CD4(+) TCM cells of RMs. Whether this relative protection from infection translates into increased stability of CD4(+) TCM cells in natural versus nonnatural hosts has not yet been determined. Here we compared, both cross-sectionally and longitudinally, the levels of CD4(+) TCM cells in a large cohort of SMs and RMs and the association between CD4(+) TCM levels and the main virologic and immunologic markers of disease progression. Consistent with their lower susceptibility to infection, CD4(+) TCM cells of SIV-infected SMs are lost with kinetics 20 times slower than those of SIV-infected RMs. Remarkably, the estimated length of time of SIV infection needed for CD4(+) TCM cells to fall to half of their initial levels is <16 months for RMs but >17 years for SMs. Furthermore, the fraction of proliferating CD4(+) TCM cells is significantly lower in SIV-infected SMs than in SIV-infected RMs, and the extent of CD4(+) TCM cell proliferation is associated positively with CD4(+) T cell levels in SIV-infected SMs but negatively with CD4(+) T cell levels in SIV-infected RMs. Collectively, these findings identify increased stability and maintenance of the prohomeostatic role of CD4(+) TCM cells as features distinguishing nonprogressive from progressive SIV infections and support the hypothesis of a direct mechanistic link between the loss of CD4(+) TCM cells and disease progression.

Importance

Comparison of the immunologic effects of simian immunodeficiency virus (SIV) infection on rhesus macaques (RMs), a species characterized by progression to AIDS, and natural host sooty mangabeys (SMs), a species which remains AIDS free, has become a useful tool for identifying mechanisms of human immunodeficiency virus (HIV) disease progression. One such distinguishing feature is that CD4(+) central memory T (TCM) cells in SIV-infected SMs are less infected than the same cells in RMs. Here we investigated whether lower levels of infection in SMs translate into a better-preserved CD4(+) TCM compartment. We found that the CD4(+) TCM compartment is significantly more stable in SIV-infected SMs. Likely to compensate for this cell loss, we also found that CD4(+) TCM cells increase their level of proliferation upon SIV infection in RMs but not in SMs, which mechanistically supports their preferential infectivity. Our study provides new insights into the importance of long-term maintenance of CD4(+) TCM homeostasis during HIV/SIV infection.

SUBMITTER: McGary CS

PROVIDER: S-EPMC3993768 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques.

McGary Colleen S CS Cervasi Barbara B Chahroudi Ann A Micci Luca L Taaffe Jessica J Meeker Tracy T Silvestri Guido G Davenport Miles P MP Paiardini Mirko M

Journal of virology 20140205 8

<h4>Unlabelled</h4>Depletion of CD4(+) central memory T (TCM) cells dictates the tempo of progression to AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) both in the natural history of infection and in the context of vaccination. CD4(+) TCM cells of sooty mangabeys (SMs), a natural host for SIV in which infection is nonpathogenic, are less susceptible to SIV infection than CD4(+) TCM cells of RMs. Whether this relative protection from infection translates into increased ...[more]

PMID: 24501416

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Project description:Transcriptional Profiling Reveals Distinguishing Features of Immune Activation in the Lymphatic Tissues of Sooty Mangabeys and Rhesus Macaques in Early SIV Infection Immune activation in the chronic stages of HIV-1 and SIV infection of rhesus macaques is thought to play a critical role in CD4+ T cell depletion and progression to AIDS. Conversely, the lack of immune activation in the chronic stages of SIV infection of sooty mangabeys is thought to protect this species from a pathogenic outcome. This critical difference in immune activation in rhesus macaques and sooty mangabeys has recently been shown to be established in the early stages of SIV infection where there is immune activation in both species, but in sooty mangabeys immune activation is subsequently resolved. Here we report the results of a microarray analysis of early SIV infection in the lymphatic tissues of rhesus macaques and sooty mangabeys that provides a comprehensive view of the distinguishing features of immune activation and host defenses in the two species. We confirm immune activation in sooty mangabeys, but show that it is less robust than in rhesus macaques, where positive feedback loops involving cytosolic pattern recognition receptors, and chemokines and their ligands amplify the response to early SIV infection. We confirm resolution of immune activation in sooty mangabeys, but show it to be partial and selective, identifying the interferon system and CD38 as key correlates of outcome. We also identify potentially novel immunoregulatory mechanisms that mediate resolution, and defensins as host defenses sooty mangabeys employ as expression of other innate immune system effectors declines. The studies we report here were undertaken in a collaborative longitudinal analysis of early SIV infection in SMs described in Bosinger et al and previously reported studies (Estes et al., J Immunol 1008, 180, 6798-6807.). Briefly, SMs were inoculated i.v. with 1 ml of plasma from an experimentally SIVsmm-infected SM sampled at day 11 post infection, with a viral load 107 copies/ml. In our studies we analyzed axillary or inguinal lymph node biopsies that had been obtained from two SMs prior to infection; two SMs at the peak of viral replication at 14 dpi; and two SMs at 30 dpi as viral loads were decreasing to set point. We analyzed axillary or inguinal LNs from 4 RMs without SIV infection and LNs from four RMs infected intravaginally with 2x105 TCID50 of SIVmac239 and sacrificed at 14 dpi the peak of viral replication from two cross-sectional studies described in (Miller et al., The Journal of Virology 2005, 79, 9217-9227.). For lymph node (LN) biopsies, animals were anesthetized with Ketamine or Telazol; the skin over the axillary or inguinal region was clipped and surgically prepped. An incision was made over the LN, which was exposed by blunt dissection and excised over clamps. A portion of the lymph node biopsy for microarray analysis was snap frozen in liquid N2. All animals were housed and cared for at the Yerkes National Primate Research Center in Atlanta, Georgia in accordance with the regulations of the American Association of Accreditation of Laboratory Animal Care standards. These studies were approved by the Emory University and University of Pennsylvania Institutional Animal Care and Usage Committees (IACUC). Microarray Analysis RNA extractions, synthesis of biotin-labeled cRNA probes, microarray hybridization, and data analysis followed previously published procedures (Li et al., The Journal of infectious diseases 2004, 189, 572-582; Li et al., J Immunol 2009, 2009, 183: 1975–1982.). Briefly, snap-frozen lymph node was homogenized in TRIzol. Total RNA was isolated and further purified. Double stranded cDNA and biotin-labeled cRNA probes were synthesized, column purified and fragmented. Fifteen micrograms of fragmented cRNA was hybridized to an Affymetrix GeneChip® Rhesus Macaque Genome Array. After hybridization, chips were washed, stained with streptavidin-phycoerythrin, and scanned with GeneChip Operating Software at the Biomedical Genomics Center at the University of Minnesota. Preparation of cRNA probes and microarray hybridizations were done in duplicate for each RNA sample. Cel. files were uploaded into the Expressionist program (Genedata, Pro version 5.1) and the expression level for each of the 47,000 transcripts in the arrays were analyzed using the RMA algorithm. The expression levels from duplicate microarrays of the same animal’s RNA were correlated and averaged. Tests for differences between the before and after infection at various time points were conducted using the 2-sample Wilcoxon signed-rank test. Fold differences in the level of gene expression between after infection and before infection were calculated with the ratio of the means. After statistical analysis, data was sorted based on these transcript cutoffs: p-value of < 0.05 and fold change ≥ 2.0. Significantly changed genes and transcripts were uploaded into NetAffix Analysis Center (http://www.affymetrix.com/analysis/index.affx) to query gene ontology information and into Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com) for gene annotation and pathway analysis. Hierarchical clustering analysis was carried out by using Spotfire for DecisionSite for Functional Genomics.

Project description:In SIV/HIV infection, the gastrointestinal tissue dominates as an important site due to the impact of massive mucosal CD4 depletion and immune activation-induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells in mediating immune activation and disease progression. We demonstrate that plasmacytoid dendritic cells (pDC) in the blood upregulate ?7-integrin and are rapidly recruited to the colorectum following a pathogenic SIV infection in rhesus macaques. These pDC were capable of producing proinflammatory cytokines and primed a Tc1 response in vitro. Consistent with the upregulation of ?7-integrin on pDC, in vivo blockade of ?4?7-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The upregulation of ?7-integrin expression on pDC in the blood was also observed in HIV-infected humans but not in chronically SIV-infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDC influence immune activation in colorectal tissue following pathogenic immunodeficiency virus infections. SIV negative controls (n=4) and week 12 post SIV infected (n=4) groups of Rhesus macaques and SIV negative controls (n=4) and week 55 post SIV infected (n=4) groups of Sooty mangabeys colorectal tissue biopsies were collected in to RNA later reagent (Qiagen) and were homogenized with syringe and needle method. RNA was extracted with Rneasy mini kit (Qiagen) and was used for microarray experiments. Rhesus GeneChip assays were performed in the Yerkes Microarray Core Facility (www.microarray.emory.edu) , one of the Affymetrix Microarray Core Labs.The 0.5µg of total RNA sample was analyzed on Rhesus Macaque Genome GeneChip that consists of over 52,000 probe sets (Affymetrix, Santa Clara, CA). Target RNA labeling, hybridization and post-hybridization processing were performed following the Affymetrix GeneChip Expression Analysis standard protocols. In brief, The 5 ?g of RNA sample was first reverse-transcribed using T7-Oligo(dT) Promoter Primer and SuperScript II in the first-strand cDNAs synthesis reaction. Following RNase H-mediated second-stranded cDNA synthesis, the double-stranded cDNAs were purified by use of a GeneChip sample clean-up module and served as templates in the generation of biotinylated complementary RNAs (cRNAs) in the presence of T7 RNA Polymerase and a biotinylated nucleotide analog/ribonucleotide mix by in vitro transcription (IVT) reaction. The biotinylated cRNAs were cleaned up, fragmented, and hybridized to the rhesus macaque expression arrays at 45°C for 16 h with constant rotation at 60 rpm. The gene chips were then washed and stained with Affymetrix fluidics stations 450 and scanned on Affymetrix scanner 3000. The images are processed to collect raw data with GeneChip Operating Software (GCOS) 1.4. Tissue: Colorectal tissue Time after SIV infection: 12 weeks for SIV infected Rhesus macaques, 55 weeks for Sooty mangabeys Infection: SIVmac251 infection for Rhesus macaques, SIVsm infection for Sooty mangabeys

Dataset Information

Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques.

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Importance

Publications

Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques.

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