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Angela Ciuffi Lab

Angela Ciuffi, PhD, MER
++41 (0)21 314 4099
++41 (0)79 556 2633
angela.ciuffi@chuv.ch

Research topics

HIV Integration, Transcription and Latency

Retroviruses use the cellular machinery throughout their life cycle to efficiently enter, integrate and bud from the host cell. Retroviruses are defined by the copy of their RNA genome into a linear double-stranded DNA, which is subsequently integrated into the host genome through the activity of the virally-encoded integrase.

In vivo integration is not random but rather favors specific regions of the cellular chromosomes, and preferences differ among retroviruses: human immunodeficiency virus (HIV) favors integration into active transcription units, murine leukemia virus (MLV) preferentially integrates into transcription start sites and CpG islands, and avian sarcoma leucosis virus (ASLV) integration favors transcription units only weakly.

The location of viral genome integration has important consequences for both the host and the virus. Indeed, retroviral integration can affect gene expression of the host cell upon insertional mutagenesis (i.e. insertion of viral promoters or enhancers near cellular genes) or gene inactivation (i.e. gene disruption caused by viral insertion). Viral gene activity can also vary according to chromosomal locations, i.e. integration in active transcription units for HIV can facilitate efficient transcription of viral genes and thus facilitate productive host infection, while integration in unfavorable DNA regions such as centromeric heterochromatin may repress viral transcription and thus impair viral replication, providing a potential mechanism for transcriptional latency.

The mechanisms underlying retroviral integration site selection begin to be elucidated. Recently, the LEDGF/p75 protein has been shown to recruit the HIV integrase to the chromatin, thereby promoting viral DNA integration into transcription units, via a tethering mechanism.

Our research focuses on the role of cellular proteins in the distribution of viral integration sites and in transcription of the viral genome with the following aims:

  • To understand the cellular function of LEDGF/p75, the first described protein involved in HIV integration site selection.
  • To identify new candidate proteins affecting retroviral integration distribution.
  • To understand the mechanisms involved in transcriptional latency.

Genetics of Human susceptibility to HIV infection and Innate immunity (collaborative project with Prof. Amalio Telenti)

Humans are not equal in terms of susceptibility to infection to HIV, or in the rate of disease progression. Our laboratory studies the basic genetic mechanisms associated with cellular and with human susceptibility to HIV. Various projects are currently conducted:

Restriction factors

Our laboratory investigates the evolution of TRIM5alpha, APOBEC3 family, SAMHD1, and a number of novel anti-hiv factors. A significant component of the research aims at reconstructing the long-range evolution of these factors in primates. In one of the approaches, we build ancestral proteins to be tested against modern retrovirus, and (ancestral) endogenous lenti- and retroviruses.

Systems biology of the viral life cycle

We use deep sequencing and modeling approaches to advance the understanding of the transcriptional re-programming of the cell upon infection. This approach is now also used to understand the factors leading to viral latency.

Pharmacogenetics of antiretroviral agents

There is considerable variation in the response to antiretroviral drugs among individuals. This concerns both the interindividual differences in pharmacokinetics, and in toxicity. Various approaches are currently used:

Analysis of genetic variation in ADME (absorption, distribution, metabolism and excretion) genes.  

Analysis of genetic variation in genes involved in lipid metabolism, cardiovascular disease, bone disease and diabetes to investigate the basis of metabolic disorders associated with aging in HIV infected patients

Translational research to move validated markers to the clinics.

These projects are supported by the Swiss National Science Foundation, the Santos Suarez Foundation, and the FP7 European program, and in the setting of the Swiss HIV Cohort Study, which includes more than 9000 individuals who have provided consent for genetic analysis.

Current members  
Name Position Contact
Paul McLaren PhD, coordinator bioinformatics paul.mclaren@epfl.ch
Margalida Rotger Pharm, PhD, Post-doc margalida.rotger@chuv.ch
Antonio Rausell PhD, Post-doc antonio.rausell@isb-sib.ch
Sylvie Ferreira Rato PhD, Post-Doc sylvie.ferreira-rato@chuv.ch
Simon Quenneville PhD, Post-Doc simon.quenneville@chuv.ch
Istvan Bartha PhD, Post-Doc istvan.bartha@epfl.ch
Nitisha Pyndiah PhD student nitisha.pyndiah@chuv.ch
Christian Thorball PhD student christian.thorball@chuv.ch
Catalina Barcelo PhD student catalina.barcelo@chuv.ch
Miguel Munoz Head Technician miguel.munoz@chuv.ch
Raquel Martinez Technician raquel.martinez@chuv.ch
Tiziano Brogna Master student tiziano.brogna@unil.ch
Jérémie Perreaud Master student jeremie.perreaud@unil.ch
Danielle Thompson Master student danielle.thompson@unil.ch

Visiting scientist                                              
Name Position Contact
Séverine Vuilleumier     PhD, research associate severine.vuilleumier@unil.ch

Research book chapters

Retroviral Integration
Target Site Selection

Viral integration and consequences
on host gene expression


Angela Ciuffi
& Frederic Bushman


Sébastien Desfarges
& Angela Ciuffi

Couverture du livre HIV-1

Couverture du livre Viruses - essential agents of life

Selected publications


2014

1: Bartha I, McLaren PJ, Ciuffi A, Fellay J, Telenti A.
    GuavaH: a compendium of host genomic data in HIV biology and disease.
Retrovirology. 2014 Jan 15;11:6.
2: Mohammadi P, di Iulio J, Muñoz M, Martinez R, Bartha I, Cavassini M, Thorball C, Fellay J, Beerenwinkel N, Ciuffi A, Telenti A.
    Dynamics of HIV Latency and Reactivation in a Primary CD4+ T Cell Model.
PLoS Pathog. 2014 May 29;10(5):e1004156.

2013

1: Ciuffi A, Telenti A.
    State of genomics and epigenomics research in the perspective of HIV cure.
Curr Opin HIV AIDS. 2013 May;8(3):176-81.
2: Mohammadi P, Desfarges S, Bartha I, Joos B, Zangger N, Muñoz M, Günthard HF, Beerenwinkel N, Telenti A, Ciuffi A.
    24 Hours in the Life of HIV-1 in a T Cell Line.
PLoS Pathog. 2013 Jan;9(1):e1003161.
3: Rahm N, Gfeller D, Snoeck J, Martinez R, McLaren PJ, Ortiz M, Ciuffi A, Telenti A.
    Susceptibility and adaptation to human TRIM5α alleles at positive selected sites in HIV-1 capsid.
Virology. 2013 Jul 5;441(2):162-70.

2011

1: Ciuffi A, Barr SD.
    Identification of HIV integration sites in infected host genomic DNA.
Methods. 2011 Jan;53(1):39-46.
2: Desfarges S, Abderrahmani A, Hernàndez-Novoa B, Munoz M, Ciuffi A.
    LEDGF/p75 TATA-less promoter is driven by the transcription factor Sp1.
J Mol Biol. 2011 Nov 25;414(2):177-93.
3: Lefebvre G, Desfarges S, Uyttebroeck F, Muñoz M, Beerenwinkel N, Rougemont J, Telenti A, Ciuffi A.
    Analysis of HIV-1 expression level and sense of transcription by high-throughput sequencing of the infected cell.
J Virol. 2011 Jul;85(13):6205-11.
4: Meylan S, Groner AC, Ambrosini G, Malani N, Quenneville S, Zangger N, Kapopoulou A, Kauzlaric A, Rougemont J, Ciuffi A, Bushman FD, Bucher P, Trono D.
    A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing.
BMC Genomics. 2011 Jul 26;12:378.
5: Rahm N, Yap M, Snoeck J, Zoete V, Muñoz M, Radespiel U, Zimmermann E, Michielin O, Stoye JP, Ciuffi A, Telenti A.
    Unique spectrum of activity of prosimian TRIM5alpha against exogenous and endogenous retroviruses.
J Virol. 2011 May;85(9):4173-83.
6: di Iulio J, Ciuffi A, Fitzmaurice K, Kelleher D, Rotger M, Fellay J, Martinez R, Pulit S, Furrer H, Günthard HF, Battegay M, Bernasconi E, Schmid P, Hirschel B, Barnes E, Klenerman P, Telenti A, Rauch A; Swiss HIV Cohort Study.
    Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.
Hepatology. 2011 May;53(5):1446-54. doi: 10.1002/hep.24263.

2010

1: Ballana E, Senserrich J, Pauls E, Faner R, Mercader JM, Uyttebroeck F, Palou E, Mena MP, Grau E, Clotet B, Ruiz L, Telenti A, Ciuffi A, Esté JA.
    ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression.
Clin Infect Dis. 2010 Apr 1;50(7):1022-32.
2: Desfarges S and Ciuffi A.
    Retroviral Integration Site Selection
Viruses 2010, 2(1), 111-130; doi:10.3390/v2010111
3: Groner AC, Meylan S, Ciuffi A, Zangger N, Ambrosini G, Dénervaud N, Bucher P, Trono D.
    KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading.
PLoS Genet. 2010 Mar 5;6(3):e1000869.

2009

1: Ciuffi A, Ronen K, Brady T, Malani N, Wang G, Berry CC, Bushman FD.
    Methods for integration site distribution analyses in animal cell genomes.
Methods. 2009 Apr;47(4):261-8.
2: Ortiz M, Guex N, Patin E, Martin O, Xenarios I, Ciuffi A, Quintana-Murci L, Telenti A.
    Evolutionary trajectories of primate genes involved in HIV pathogenesis.
Mol Biol Evol. 2009 Dec;26(12):2865-75.

2008

1: Ciuffi A.
    Mechanisms governing lentivirus integration site selection.
Curr Gene Ther. 2008 Dec;8(6):419-29.
2: Goldschmidt V, Ciuffi A, Ortiz M, Brawand D, Muñoz M, Kaessmann H, Telenti A.
    Antiretroviral activity of ancestral TRIM5alpha.
J Virol. 2008 Mar;82(5):2089-96.
3: Wang GP, Garrigue A, Ciuffi A, Ronen K, Leipzig J, Berry C, Lagresle-Peyrou C, Benjelloun F, Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M, Bushman FD.
    DNA bar coding and pyrosequencing to analyze adverse events in therapeutic gene transfer.
Nucleic Acids Res. 2008 May;36(9):e49

2007

1: Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD
    HIV integration site selection: Analysis by massively parallel pyrosequencing reveals association with epigenetic modifications.
Genome Res. 2007 Aug;17(8):1186-1194.

2006

1: Angela Ciuffi and Richard S. Mitchell, Christian Hoffmann, Jeremy Leipzig, Paul Shinn, Joseph R. Ecker, and Frederic D. Bushman
    Integration site selection by HIV-based vectors in dividing and growth-arrested IMR-90 lung fibroblasts
Molecular Therapy 13(2): 366-373.
2: Ciuffi A, Bushman FD.
    Retroviral DNA integration : HIV and the role of LEDGF/p75
Trends in Genetics 12 (7): 388-395.
3: Ciuffi A, Diamond TL, Hwang Y, Marshall HM, Bushman FD.
    Modulating target site selection during human immunodeficiency virus DNA integration in vitro with an engineered tethering factor.
Human Gene Therapy 17 (9): 960-967.

2005

1: Ciuffi A., Llano M., Poeshla E., Marshall H., Hoffmann C., Shinn P., Hannenhalli S., Ecker J., and Bushman
    A role for LEDGF/p75 in targeting HIV DNA integration
Nature Medicine 11(12): 1287-1289.
2: Frederic Bushman, Mary Lewinski, Angela Ciuffi, Stephen Barr, Jeremy Leipzig, Sridhar Hannenhalli and Christian Hoffmann
    Genome-wide analysis of retroviral DNA integration
Nature Reviews Microbiology 3 (11): 848-858.

2004

1: Ciuffi A., Bleiber G., Munoz M., Martinez R., Loeuillet C., Rehr M., Fischer M., Gunthard H.F., Oxenius A., Meylan P., Bonhoeffer S., Trono D., and Telenti A.
    Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection
Journal of Virology 78(19):10747-10754


Last Update on 01.09.2014 - Publication credits - Legal information