Reactivating and characterizing replication

ED BIO SORBONNE PARIS CITE Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : Inserm U941, Génétique des Virus et Pathogénèse des Maladies Virales
Nom et prénom du Directeur : CLAVEL François
Téléphone :
01 57 27 67 64
Télécopie :
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Evolution et Pathogénèse Virales
Nom et prénom du responsable : MAMMANO Fabrizio
Qualité du responsable : DR2 Inserm
Téléphone :
01 57 27 67 57
Télécopie :
Courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : MAMMANO Fabrizio
Qualité : DR2 Inserm
Téléphone :
01 57 27 67 57
Télécopie :
Courriel : [email protected]
Titre du sujet proposé :
Réactivation et caractérisation des génomes VIH infectieux issus du réservoir des cellules T
Reactivating and characterizing replication-competent HIV genomes from the T-cell reservoir Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lines maximum) :
Potent antiretroviral treatment successfully suppresses HIV replication in most patients, but is ineffective
against transcriptionally silent proviruses that constitute the viral reservoirs. Recent data suggest that
viral genomes that do not undergo high-level transcription have higher chances of persisting in the latent
reservoir. Our project aims at exploring differences in the intensity of viral latency in patients with
different treatment histories.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
(L’ensemble de cette fiche ne doit pas dépasser 1 page)
Nom, prénom du directeur de l'unité de recherche : CLAVEL François
Numéro de l'unité de recherche (et établissement de rattachement) : Inserm U941, Hôpital Saint-Louis
Nom, prénom du responsable de l'équipe d'accueil (EAD) : MAMMANO Fabrizio
Nom, prénom du directeur de thèse : MAMMANO Fabrizio
Titre du sujet de thèse proposé :
Reactivating and characterizing replication-competent HIV genomes from the T-cell reservoir
Citer 5 mots clés : HIV-1, latency, reservoirs, antiretroviral treatment, persistance
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
One of the main obstacles to HIV cure is the persistence of a large reservoir of integrated HIV
genomes in memory CD4 T-cells. This reservoir is established early in the course of the infection in vivo,
appears to be insensitive to the action of antiretroviral drugs, and is thought to be the principal source of
the resurgence of HIV replication after interruption of antiretroviral treatment (ART). HIV integration is
favored in loci of the host genome that are transcriptionally active, a pattern that facilitates optimal
expression of HIV following stimulation of T-cells. In quiescent T-cells, however, HIV transcription
remains generally silent.
In vivo, most T-cell clones are bound to experience some level of antigen-driven stimulation and
homeostatic cell division, potentially leading to expression of HIV antigens. Since T-cells in which the
expression of HIV antigens is more easily triggered are more likely to be eliminated (by immune
responses or intrinsic viral toxicity), it is reasonable to assume that the duration of suppressive ART
could lead to the selection of proviruses that are in a state of deeper latency and transcriptional
silencing.
We propose that the HIV T-cell reservoir must be viewed not only in terms of its size and nature,
but also in terms of the depth and intensity of HIV transcriptional silencing. For some latent HIV
genomes, transcription could be easy to stimulate through the regular transcriptional activation
pathways, such as TCR stimulation. In others, transcription could be intrinsically hindered, and require
more potent exogenous stimulation to be relieved.
We will test these hypotheses, by comparing the requirements for different stimulations ex vivo
for induction and virus outgrowth. We will explore these properties in CD4+ lymphocytes from the
peripheral blood of patients with different treatment duration, to elucidate potential associations. Our
study aims at disclosing and quantifying the depth of latency, a neglected dimension of the HIV T-cell
reservoir.
Indiquez les cinq meilleures publications récentes de l’équipe :
- HIV cell-to-cell transmission requires the production of infectious virus particles, and does not proceed through
Env-mediated fusion pores. Journal of Virology, 2012 (PMID: 22258237). Monel B., Beaumont E., Vendrame D.,
Schwartz O., Brand D., and Mammano F.
- Impact of the HIV integrase genetic context on the phenotypic expression and in vivo emergence of raltegravir
resistance mutations. J. of Antimicrobial Chemotherapy, 2014 (PMID: 25336162). Nguyen T.T.N., Rato S. Molina
J.M., Clavel F., Delaugerre C., Mammano F.
- Quantifying the Antiviral Effect of IFN on HIV-1 Replication in Cell Culture. Scientific Reports (Nature Pub. Group)
2015 (PMID: 26119462). Ikeda H., Godinho-Santos A., Rato S., Vanwalscappel B., Clavel F., Aihara K., Iwami S.,
Mammano F.
- Cell-to-cell infection by HIV contributes over half of virus infection. Elife. 2015 (PMID: 26441404). Iwami S.,
Takeuchi J.S., Nakaoka S., Mammano F., Clavel F., Inaba H., Kobayashi T., Misawa N., Aihara K., Koyanagi Y,
and Sato K.
- Kinetics of the establishment of HIV-1 viral interference and comprehensive analysis of the contribution of viral
genes. Virology 2016 (PMID: 26499042). Remion A., Delord M., Hance A.J., Saragosti S., and Mammano F.