Génétique des virus et pathogenèse des maladies virales Equipe 1

 UMR 941 – Génétique des virus et pathogenèse des maladies virales Equipe 1 - VIRUS EVOLUTION AND PATHOGENESIS /
EVOLUTION ET PATHOGENESE VIRALES
CHEF D’EQUIPE
Fabrizio MAMMANO, DR2 Inserm
Tél. : 33 (0)1 57 27 67 57
Email: fabrizio.mammano@inserm.fr
Secrétariat : Arlette Malepou Tél. : 33 (0)1 57 27 67 58 Email : arlette.malepou@inserm.fr Adresse : Inserm U941, Institut Universitaire d’Hématologie, Bâtiment Hayem,
3e étage
Hôpital Saint-Louis, 1, avenue Claude Vellefaux,
F-75010 Paris
THEMES DE RECHERCHE
Overview
We are interested in different aspects of HIV (Human Immunodeficiency Virus)
and hCMV (human cytomegalovirus) replication, evolution and pathogenesis. The
main research axes are described here below. In our group, researchers
interested in molecular and cellular virology work together with clinical
investigators focused on virus pathogenesis and treatment strategies. Research
facilities are located within the IUH (Institut Universitaire d’Hématologie), and at
the Hospital (Clinical Infectious Disease Department, and Microbiology
Department).
1)
HIV evolution under the selective pressure of IFN in treated
patients
Type-I interferons (IFN) are known to inhibit both early and late steps of HIV-1
replication in vitro, by inducing the expression of several proteins endowed with
antiviral properties. We have initially studied the potency of IFN inhibition in tissue
culture, and the potential virus escape strategies. We are currently exploring how
HIV evolves under the selective pressure of IFN in treated patients, by analyzing
the evolution of HIV populations in HIV-HCV co-infected patients who were not
treated for HIV, and received Peg-IFN for HCV. Changes in the composition of HIV
populations over-time were analyzed by deep-sequencing in collaboration with the
team of Jose Alcami (Madrid). This analysis provided quantification of the
frequency of viral gene variants at different time points. Their phenotypic impact
on IFN resistance is being determined.
2)
HIV reservoirs in treated patients
One of the major hurdles to HIV eradication is the early establishment of viral
reservoirs in infected patients. Viral reservoirs consist of cells carrying a stably
integrated latent HIV genome, whose expression can be reactivated. Different
strategies aimed at accelerating the clearance of the latent reservoir are currently
undergoing clinical trials. A central question for the design of such studies is how
to measure the impact of the treatment on the latent reservoir. Different
approaches were developed, based on DNA measurement or viral outgrowth
assays, each of which has specific advantages and drawbacks. By using different
technologies, we aim at exploring the initial seeding of the reservoir in newly
infected patients, and its modulation by specific intervention strategies.
3)
HIV-induced resistance to super-infection: kinetics and viral factors
involved
Viral interference is a phenomenon by which a virus-infected cell displays reduced
susceptibility to a second infection. Double-infections, however, allows genetic
recombination, contributing to HIV diversity, evolution, and pathogenesis. Thus,
while HIV can clearly induce interference, under some circumstances, this
phenomenon appears to be regulated. Recent work from our group allowed to
compare the kinetics and potency of receptor-dependent and – independent
interference, and to identify the key viral gene responsible for potent early
interference. The characterization of the mechanism is under investigation.
4)
Impact of cell-to-cell transmission on CMV tropism
Human Cytomegalovirus (CMV) is a major pathogen for immune compromised
patients, in particular the recipients of organ transplantation and of hematopoietic
stem cells. Having previously explored some of the mechanism and advantages of
virus cell-to-cell transmission for HIV, we are investigating whether this process
participates to the complex cellular tropism of CMV. This work is conducted within
the national reference center for CMV, and focuses on primary, clinically relevant,
CMV isolates.
L'EQUIPE Our research team consists of a group of experimental researchers who apply
molecular and cell-biology approaches to study HIV replication and evolution, and
a group of clinical virologists, based at the Hospital, conducting clinical research on
HIV prevention, treatment and pathogenesis.
Fabrizio MAMMANO, DR-2 Inserm
Sentob SARAGOSTI, DR-2 Inserm
Marie-Christine MAZERON, MCU-PH (Univ. Paris 7)
Bénédicte VANWASCAPPEL, PhD student (Univ. Paris 7)
Ana GODINHO-SANTOS, PhD Student (Univ. Lisbon)
Julie MIGRAINE, Assistant Engineer, Inserm (50%)
Équipe émergente: HIV Physiopathology
Constance DELAUGERRE, MCU-PH (Univ. Paris 7)
Marie-Laure CHAIX, MCU-PH (Univ. Paris 7)
Sébastien GALLIEN, MCU-PH (Univ. Paris 7)
Géraldine GAUBE, M2 Student (Univ. Paris 7)
Héloïse DELAGREVERIE, Med. Student (Univ. Paris 7)
Jean-Michel MOLINA, Professor, PU-PH (Univ. Paris 7)
SELECTION DE PUBLICATIONS
HIV cell-to-cell transmission requires the production of infectious virus particles and does not
proceed through env-mediated fusion pores.
Monel B, Beaumont E, Vendrame D, Schwartz O, Brand D, Mammano F.
Journal of Virology, 2012, PMID: 22258237
Hyperthermia stimulates HIV-1 replication.
Roesch F, Meziane O, Kula A, Nisole S, Porrot F, Anderson I, Mammano F, Fassati A, Marcello A,
Benkirane M, Schwartz O.
PLoS Pathogens, 2012, PMID: 22807676
Counteraction of tetherin antiviral activity by two closely related SIVs differing by the presence of
a Vpu gene.
Nikovics K, Dazza MC, Ekwalanga M, Mammano F, Clavel F, Saragosti S.
PLoS One, 2012, PMID: 22530020
Innate sensing of HIV-infected cells.
Lepelley A, Louis S, Sourisseau M, Law HK, Pothlichet J, Schilte C, Chaperot L, Plumas J, Randall
RE, Si-Tahar M, Mammano F, Albert ML, Schwartz O.
PLoS Pathogens, 2011, PMID: 21379343
Impact of the HIV integrase genetic context on the phenotypic expression and in vivo emergence
of raltegravir resistance mutations.
Nguyen TT, Rato S, Molina JM, Clavel F, Delaugerre C, Mammano F.
Journal of Antimicrobial Chemotherapy, 2014, PMID: 25336162
Archived HIV-1 DNA resistance mutations to rilpivirine and etravirine in successfully treated HIV1-infected individuals pre-exposed to efavirenz or nevirapine.
Gallien S, Charreau I, Nere ML, Mahjoub N, Simon F, de Castro N, Aboulker JP, Molina JM,
Delaugerre C
Journal of Antimicrobial Chemotherapy, 2014
Safety and efficacy of coformulated efavirenz/emtricitabine/tenofovir single-tablet regimen in
treatment-naive patients infected with HIV-1.
Gallien S, Flandre P, Nguyen N, De Castro N, Molina JM, Delaugerre C.
Journal of Medical Virology 2014, PMID: 25070158