Regulation of Retroviral Infections  


  HEADProfesseur Françoise BARRE-SINOUSSI / fbarre@pasteur.fr
  MEMBERSARNOLD Vincent Thésard / BARRE-SINOUSSI Françoise Professeur, Chef d’Unité / BERGAMASCHI Anna Dr, Post-doc / CANNOU Claude Technicien, aide de laboratoire / DAVID Annie Dr, Ingénieur / DELAIRE Marie-Claire Aide de laboratoire (mi-temps) / DIDIER Céline Technicien supérieur / JACQUELIN Béatrice Dr, Ingénieur / JOULLIE Magali Secrétaire de Direction / KUNKEL Désirée Dr, Post-doc / LIOVAT Anne-Sophie Thésarde / MARLIN Romain Thésard
MAYAU Véronique Technicienne supérieur / MENU Elisabeth Dr, Chargée de Recherche / MULLER-TRUTWIN Michaela Dr, Chargée de Recherche / NUGEYRE Marie-Thérèse Ingénieur / PANCINO Gianfranco Dr, Directeur de Recherche / ROSS Anna-Laura Dr, Post-doc / SAEZ-CIRION Asier Dr, Assistant de recherche / SCOTT-ALGARA Daniel Dr, Chef de laboratoire / SHIN So-youn Thésarde / VERSMISSE Pierre Technicien supérieur / WEISS Laurence Professeur, Université Paris V (20%) / YARBROUGH Kevin Etudiant en médecine


  Annual Report

Unlike most other persistent viruses, HIV-1 progressively destroys the immune system, resulting in AIDS by very complex mechanisms that remain to be elucidated. Our laboratory is conducting research on the precise mechanisms underlying HIV/SIV pathogenesis and its control, specifically on cellular restriction mechanisms that may limit viral replication and on regulation by immune mechanisms, including critical components of the innate immunity, that may participate to harmful or favorable immune stimulation, using different models either in vitro or in human and non-human primates.

1-Regulation of viral replication by cellular restriction mechanisms.

Our investigations on host cells permissive or not to HIV-1 infection demonstrated that:

- the resistance of CD4+ T lymphocytes from HIV-1 highly exposed uninfected individuals (EU) implies constitutive mechanisms affecting either HIV-1 entry (low CCR5 co-receptor expression associated with heterozygous CCR5 mutations or elevated sensitivity to β-chemokines) or post-entry steps of replication of HIV-1 and of other retroviruses.

- the engagement of activating FcγR on macrophage surface suppresses lentiviral replication (HIV-1 as well HIV-2, SIVmac and SIVagm) by reducing viral reverse transcript levels and integration.

- despite viral entry, placental trophoblast cells are restricted to infection by cell-free HIV-1 and restriction implies, at least, viral env determinants.

2- Regulation mediated by immune mechanisms, including components of the innate immunity.

Our recent investigations on both innate and adaptive immune regulations indicated that:

- HIV-specific CD8+ T cells from HIV-1-infected individuals who remain with undetectable viremia in the absence of therapy (HIV controllers) exhibit a unique activation phenotype (CD38-HLA DR+) and are capable to suppress HIV infection in vitro by eliminating infected CD4+ T cells.

- non-pathogenic SIV infection in African Green Monkeys (AGM) correlates with a very rapid control of harmful T cell activation associated with a significant increase of plasmacytoid dendritic cells (pDC) in lymph nodes together with heightened levels of IFNα, of anti-inflammatory responses (TGFβ-1, IL10) and of markers of T regulatory cells like FoxP3.

- elevated levels of TNF-α are contributing to an increasing risk of HIV-1 transmission at the materno-fetal interface, according to data on the reduction of placental TNF-α by preventive antiviral therapy (AZT) and on the increased HIV-1 replication related to TNF-α induction by a Plasmodium falciparumantigen in placental cells.

- Natural Killer (NK) cell activation observed constitutively in HIV-1 highly Exposed Uninfected individuals (EUs) or in response to infected dendritic cells (DCs) might contribute to a protective immune response to HIV-1 through the expression of particular NK cell receptors.

Keywords: HIV, SIV, Innate Immunity, natural killer cell, dendritic cell, macrophage, mother to child transmission, elite controllers, immune activation, protection



  Publications

RAVET S, SCOTT-ALGARA D, BONNET E, TRAN HK, TRAN T, NGUYEN N, TRUONG XL, THEODOROU I, BARRE-SINOUSSI F, PANCINO G& PAUL P. Distinctive NK cell receptor repertoires sustain high-level constitutive NK cell activation in HIV-exposed uninfected individuals.

Blood2007, 109(10), 4296-305.

SAEZ-CIRION A, LACABARATZ C, LAMBOTTE O, VERSMISSE P, URRUTIA A, BOUFASSA F, BARRE-SINOUSSI F, DELFRAISSY JF, SINET M, PANCINO G & VENET A. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar CTL activation phenotype.

Proc Natl Acad Sci USA 2007104, 6776-6781

KFUTWAH A., MARY J.Y., NICOLA M.A., BLAISE-BOISSEAU S., BARRE-SINOUSSI F., AYOUBA A. & MENU E . Tumour necrosis factor-αstimulates HIV-1 replication in single-cycle infection of human term placental villi fragments in a time, viral dose and envelope dependent manner.

Retrovirology 2006 ; 3 : 37

DAVID A., SAEZ-CIRION A., VERSMISSE P. MALBEC O., IANNASCOLI B., HERSCHKE F. LUCAS M., BARRE-SINOUSSI F., MOUSCADET J.F., DAERON M. & PANCINO G. The engagement of activating Fcγreceptors inhibits primate lentivirus replication in human macrophages

J. Immunol.2006, 177:6291-300

KORNFELD C., PLOQUIN M.J., PANDREA I., FAYE A., ONANGA R., APETREI C., POATY-MAVOUNGOU V., ROUQUET P., ESTAQUIER J., MORTARA L., DESOUTTER J.F., BUTOR C., LEGRAND R., ROQUES P., SIMON F., BARRE-SINOUSSI F., DIOP O.M. & MULLER-TRUTWIN M.C. Anti-inflammatory Profiles during Primary SIVagm Infection are associated with Protection against AIDS

Journal of Clinical Investigation. 2005 ; 115 (4) : 1082-1091





Activity Reports 2007 - Institut Pasteur
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