Genome-Wide mRNA Expression Correlates of Viral Control in CD4+ T-Cells from HIV-1-Infected Individuals
There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control.
Vyšlo v časopise:
Genome-Wide mRNA Expression Correlates of Viral Control in CD4+ T-Cells from HIV-1-Infected Individuals. PLoS Pathog 6(2): e32767. doi:10.1371/journal.ppat.1000781
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1000781
Souhrn
There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control.
Zdroje
1. TelentiA
GoldsteinDB
2006 Genomics meets HIV. Nat Rev Microbiol 4 9 18
2. FellayJ
ShiannaKV
GeD
ColomboS
LedergerberB
2007 A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1. Science 317 944 947
3. DalmassoC
CarpentierW
MeyerL
RouziouxC
GoujardC
2008 Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study. PLoS ONE 3 e3907 doi:10.1371/journal.pone.0003907
4. LimouS
LeCS
CoulongesC
CarpentierW
DinaC
2009 Genomewide Association Study of an AIDS-Nonprogression Cohort Emphasizes the Role Played by HLA Genes (ANRS Genomewide Association Study 02). J Infect Dis 199 419 426
5. FellayJ
GeD
ShiannaKV
ColomboS
LedergerberB
2009 Common Genetic Variation and the Control of HIV-1 in Humans. PLoS Genet 5 e1000791 doi:10.1371/journal.pgen.1000791
6. GiriMS
NebozhynM
ShoweL
MontanerLJ
2006 Microarray data on gene modulation by HIV-1 in immune cells: 2000–2006. J Leukoc Biol 80 1031 1043
7. SedaghatAR
GermanJ
TeslovichTM
CofrancescoJJr
JieCC
2008 Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics. J Virol 82 1870 1883
8. HyrczaMD
KovacsC
LoutfyM
HalpennyR
HeislerL
2007 Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells. J Virol 81 3477 3486
9. ChunTW
JustementJS
LempickiRA
YangJ
DennisGJr
2003 Gene expression and viral prodution in latently infected, resting CD4+ T cells in viremic versus aviremic HIV-infected individuals. Proc Natl Acad Sci U S A 100 1908 1913
10. ImbeaultM
OuelletM
TremblayMJ
2009 Microarray study reveals that HIV-1 induces rapid type-I interferon-dependent p53 mRNA up-regulation in human primary CD4+ T cells. Retrovirology 6 5
11. GiriMS
NebozyhnM
RaymondA
GekongeB
HancockA
2009 Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance. J Immunol 182 4459 4470
12. NicaAC
DermitzakisET
2008 Using gene expression to investigate the genetic basis of complex disorders. Hum Mol Genet 17 R129 R134
13. VeyrierasJB
KudaravalliS
KimSY
DermitzakisET
GiladY
2008 High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4 e1000214 doi:10.1371/journal.pgen.1000214
14. BowieAG
UnterholznerL
2008 Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol 8 911 922
15. OrtizM
GuexN
PatinE
MartinO
XenariosI
2009 Evolutionary Trajectories of Primate Genes Involved in HIV Pathogenesis. Mol Biol Evol 26 2865 2875
16. BrassAL
DykxhoornDM
BenitaY
YanN
EngelmanA
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science 319 921 926
17. KonigR
ZhouY
EllederD
DiamondTL
BonamyGM
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135 49 60
18. ZhouH
XuM
HuangQ
GatesAT
ZhangXD
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe 4 495 504
19. YeungML
HouzetL
YedavalliVS
JeangKT
2009 A genome-wide short hairpin RNA screening of jurkat T-cells for human proteins contributing to productive HIV-1 replication. J Biol Chem 284 19463 19473
20. LiQ
SmithAJ
SchackerTW
CarlisJV
DuanL
2009 Microarray analysis of lymphatic tissue reveals stage-specific, gene expression signatures in HIV-1 infection. J Immunol 183 1975 1982
21. HeinzenEL
GeD
CroninKD
MaiaJM
ShiannaKV
2008 Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol 6 e1000001 doi:10.1371/journal.pbio.1000001
22. Bonnevie-NielsenV
FieldLL
LuS
ZhengDJ
LiM
2005 Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. Am J Hum Genet 76 623 633
23. LimJK
LiscoA
McDermottDH
HuynhL
WardJM
2009 Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLoS Pathog 5 e1000321 doi:10.1371/journal.ppat.1000321
24. ZolotukhinAS
FelberBK
1997 Mutations in the nuclear export signal of human ran-binding protein RanBP1 block the Rev-mediated posttranscriptional regulation of human immunodeficiency virus type 1. J Biol Chem 272 11356 11360
25. FinkJ
GuF
LingL
TolfvenstamT
OlfatF
2007 Host gene expression profiling of dengue virus infection in cell lines and patients. PLoS Negl Trop Dis 1 e86 doi:10.1371/journal.pntd.0000086
26. LongHT
HibberdML
HienTT
DungNM
VanNT
2009 Patterns of gene transcript abundance in the blood of children with severe or uncomplicated dengue highlight differences in disease evolution and host response to dengue virus infection. J Infect Dis 199 537 546
27. SimmonsCP
PopperS
DolocekC
ChauTN
GriffithsM
2007 Patterns of host genome-wide gene transcript abundance in the peripheral blood of patients with acute dengue hemorrhagic fever. J Infect Dis 195 1097 1107
28. UbolS
MasrinoulP
ChaijaruwanichJ
KalayanaroojS
CharoensirisuthikulT
2008 Differences in global gene expression in peripheral blood mononuclear cells indicate a significant role of the innate responses in progression of dengue fever but not dengue hemorrhagic fever. J Infect Dis 197 1459 1467
29. WuJQ
DwyerDE
DyerWB
YangYH
WangB
2008 Transcriptional profiles in CD8+ T cells from HIV+ progressors on HAART are characterized by coordinated up-regulation of oxidative phosphorylation enzymes and interferon responses. Virology 380 124 135
30. WenW
ChenS
CaoY
ZhuY
YamamotoY
2005 HIV-1 infection initiates changes in the expression of a wide array of genes in U937 promonocytes and HUT78 T cells. Virus Res 113 26 35
31. HerbeuvalJP
ShearerGM
2007 HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 123 121 128
32. ReinhartTA
FallertBA
PfeiferME
SanghaviS
CapuanoSIII
2002 Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. Blood 99 3119 3128
33. AbelK
Alegria-HartmanMJ
RothaeuslerK
MarthasM
MillerCJ
2002 The relationship between simian immunodeficiency virus RNA levels and the mRNA levels of alpha/beta interferons (IFN-alpha/beta) and IFN-alpha/beta-inducible Mx in lymphoid tissues of rhesus macaques during acute and chronic infection. J Virol 76 8433 8445
34. KhatissianE
ToveyMG
CumontMC
MonceauxV
LebonP
1996 The relationship between the interferon alpha response and viral burden in primary SIV infection. AIDS Res Hum Retroviruses 12 1273 1278
35. BosingerSE
HosiawaKA
CameronMJ
PersadD
RanL
2004 Gene expression profiling of host response in models of acute HIV infection. J Immunol 173 6858 6863
36. LedererS
FavreD
WaltersKA
ProllS
KanwarB
2009 Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 5 e1000296 doi:10.1371/journal.ppat.1000296
37. MandlJN
BarryAP
VanderfordTH
KozyrN
ChavanR
2008 Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 14 1077 1087
38. SatoT
OnaiN
YoshiharaH
AraiF
SudaT
2009 Interferon regulatory factor-1 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med doi:10.1038/nm.1973
39. BoassoA
ShearerGM
2008 Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol 126 235 242
40. BushmanFD
MalaniN
FernandesJ
D'OrsoI
CagneyG
2009 Host cell factors in HIV replication: meta-analysis of genome-wide studies. PLoS Pathog 5 e1000437 doi:10.1371/journal.ppat.1000437
41. TelentiA
2009 HIV-1 host interactions - integration of large scale datasets. F1000 Biology Reports 1 71
42. MartinMP
DeanM
SmithMW
WinklerC
GerrardB
1998 Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science 282 1907 1911
43. GeissGK
BumgarnerRE
BirdittB
DahlT
DowidarN
2008 Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 26 317 325
44. SwansonCM
MalimMH
2008 SnapShot: HIV-1 proteins. Cell 133 742, 742
45. GoffSP
2007 Host factors exploited by retroviruses. Nat Rev Microbiol 5 253 263
46. NisoleS
StoyeJP
SaibA
2005 TRIM family proteins: retroviral restriction and antiviral defence. Nat Rev Microbiol 3 799 808
47. HarrisRS
LiddamentMT
2004 Retroviral restriction by APOBEC proteins. Nat Rev Immunol 4 868 877
48. LoeuilletC
DeutschS
CiuffiA
RobyrD
TaffeP
2008 In vitro whole-genome analysis identifies a susceptibility locus for HIV-1. PLoS Biol 6 e32 doi:10.1371/journal.pbio.0060032
49. NeilSJ
ZangT
BieniaszPD
2008 Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451 425 430
50. DunningMJ
Barbosa-MoraisNL
LynchAG
TavareS
RitchieME
2008 Statistical issues in the analysis of Illumina data. BMC Bioinformatics 9 85
51. LinSM
DuP
HuberW
KibbeWA
2008 Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36 e11
52. DuP
KibbeWA
LinSM
2008 lumi: a pipeline for processing Illumina microarray. Bioinformatics 24 1547 1548
53. SmythGK
2004 Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3 Article3
54. FengS
WolfingerR
ChuZ
GibsonG
McGrawL
2006 Empirical Bayesian analysis of variance component models for microarray data. J Agric Biol Environ Stats 11 197 209
55. LönnstedtI
SpeedT
2002 Replicated microarray data. Stat Sinica 12 31 46
56. BenjaminiY
HochbergY
1995 Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 57 289
57. DennisGJr
ShermanBT
HosackDA
YangJ
GaoW
2003 DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4 3
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 2
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Caspase-1 Activation via Rho GTPases: A Common Theme in Mucosal Infections?
- Kaposi's Sarcoma Associated Herpes Virus (KSHV) Induced COX-2: A Key Factor in Latency, Inflammation, Angiogenesis, Cell Survival and Invasion
- IL-1β Processing in Host Defense: Beyond the Inflammasomes
- Reverse Genetics in Predicts ARF Cycling Is Essential for Drug Resistance and Virulence