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  Bioret


  Director : Françoise BARRÉ-SINOUSSI (fbarre@pasteur.fr)


  abstract

 

Our Unit is conducting research on viral and host determinants of HIV/AIDS, using different approaches

  • Mother to child transmission (MTCT) as a model to study the selective forces involved in controlling the passage of HIV1 across a cellular barrier, the placenta.
  • Infection within the thymus to study the impact of a lymphoid environment on HIV replication and lymphoid cell survival.
  • Infection of African Green Monkeys (AGMs) by SIVagm as a model of protection against AIDS.
  • Exposed non-infected individuals (ENI) to approach host determinants of protection against HIV1 infection, in particular, in the context of persistent immune activation in Africa and Asia.



  report

cale

I/ Study of the mechanisms involved in the control of HIV-1 in utero transmission: a model to study the regulation of the passage of the virus through a cellular barrier. Group leader : Elisabeth MENU

The placental environment is involved in the establishment and maintenance of pregnancy as well as in the control of in utero infection of the fetus, probably through soluble factors such as inflammatory cytokines, Th1- and Th2-type cytokines or chemokines. This project aims to study, in the framework of an international network, the role of the placental environment in the control of in utero HIV-1 transmission and the mechanisms involved in this natural protection against infection. Several complementary approaches are developed: ex vivo studies to determine the effect on the placental environment of HIV-1 infection and of distinct preventive antiretroviral treatment regimens (type and duration) provided to HIV-1 positive pregnant women, an in vitro model of a trophoblast barrier reconstitution and a placental histoculture system.

II/ Control of HIV-1 replication and of survival of thymocytes upon infection within the thymus. Group leader: Nicole ISRAEL.

Interaction of human thymocytes with thymic epithelial cells (TEC) was previously shown to induce HIV replication within the thymus. This interaction leads to co-secretions of two cytokines crucial for viral replication, namely TNF and IL-7. However this interaction is efficient only with mature CD4+thymocytes. In other thymocyte subpopulations, viral replication is restricted either because of their unresponsiveness to the cytokines (double-positive CD4+CD8+ cells) or of a lack of TNF secretion (intermediate CD4+CD8-CD3- thymocytes). However, the lack of TNF might be compensated by the TNF secreted by activated macrophages that infiltrate the thymus in response to infection. TNF is required to induce NF-kB activity and, consequently, virus transcription whereas IL-7 is a necessary cofactor to induce the TNF receptor (TNFR2). Furthermore, the mature CD4+thymocytes exhibit a high survival capacity despite the production of a high yield of viruses. Indeed, IL-7 confer a high resistance to infection induced apoptosis by sustaining a high level of the anti-apoptotic molecule Bcl-2. In contrast, intermediate thymocytes, which replicate the virus at a lower level, are more sensitive to apoptosis, and their differentiation increases their death rate upon infection. This sensitivity is related to lower expression levels of the IL-7 receptor (IL-7R) and of Bcl-2. In addition, the infection itself increases Bcl-2 expression in the mature cells whereas it decreases this level in intermediate cells. Finally, IL7 is inducing an up-regulation of CXCR4 and, consequently, favors X4 virus replication, in particular in mature thymocytes. Altogether these data suggest that in vivo, HIV infection might create a persistent reservoir of X4 viruses within the mature CD4+ thymocytes whereas the later infection of intermediate cells might lead to thymopoiesis failure.

III/ Early host determinants of protection against AIDS in African Green Monkeys.

Group leader: Michaela MÜLLER-TRUTWIN

The infection of African Green monkeys (AGM) by a simian lentivirus (SIV) is used as a model to study natural protection against AIDS. This study is performed in collaboration with the Pasteur Institute International Network. Our previous data indicate a long presence of SIVagm in AGMs and a co-evolution of the virus and its host. We demonstrate that the absence of pathology is not associated with a selection of viral variants attenuated for replication. We rather observe high levels of virus in the blood, which are similar to that described in HIV-1 infected humans. Despite the persistent replication, that reaches in some animals the same elevated levels as in pathogenic infections, no signs of chronic T cell activation in the lymph nodes, such as follicular hyperplasia or infiltration of CD8+ cells into germinal centers are observed. Differences in early T cell activation profiles might be associated with the distinct outcomes of SIVagm and HIV-1 infections. The role of the early interactions between dendritic cells and T cells during the non-pathogenic SIVagm infection is currently under investigations.

 

IV/ Determinants of natural protection against HIV-1 infection. Group leader: Gianfranco PANCINO

Our research aims to identify and characterize immune factors of natural protection against HIV-1. This question is addressed by studying HIV-1-exposed but uninfected individuals uninfected (EU) in the specific genetic and environmental context of Asian and African populations. Their persistent exposure to infectious agents affects immune activation and immune responses and, thus their immune background might, in certain cases, contribute to their protection against HIV-1. In such a context, both innate and specific immune responses could be key determinants for protection. Cohorts of systemically (IVDUs) or sexually (seronegative partners of seropositive individuals) exposed EUs have been enrolled in Ho Chi Minh City (Vietnam), Phnom Penh (Cambodia) and Bangui (Central African republic), in collaboration with the Pasteur Institute International Network. Our studies specially focus on molecular mechanisms involved in a resistance of EU cells to HIV-1 ex vivo and on Natural Killer response in EU (in collaboration with D. Scott-Algara). In parallel, we are also studying the impact of macrophage activation on their susceptibility to HIV-1 infection, using a model of activation and infection of primary human monocyte derived macrophages (MDM). We recently demonstrated that macrophage activation by Immunoglobulin Fc receptors (FcgR) cross-linking inhibits HIV-1 replication in MDM, independently of the viral tropism.



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
 

Sylviane GUESDON-CAYRE (cayre@pasteur.fr)

BARRÉ-SINOUSSI Françoise (Researcher), fbarre@pasteur.fr

ISRAËL Nicole (Researcher), nisrael@pasteur.fr

MENU Elisabeth (Researcher), emenu@pasteur.fr

MÜLLER-TRÜTWIN Michaela (Researcher), mmuller@pasteur.fr

PANCINO Gianfranco (Researcher), gpancino@pasteur.fr

BEQ Stephanie (Ph.D. Student), sbeq@pasteur.fr

CHARRAD Sihem (post-doc), scharrad@pasteur.fr

DERRIEN Muriel (post-doc), mderrien@pasteur.fr

DOLCINI Guillermina (Ph.D. student), guidol@pasteur.fr

GUILLEMARD Eric (post-doc), eguillem@pasteur.fr

KORNFELD Christopher (Ph.D. student), ckornfel@pasteur.fr

PEREZ-BERCOFF Danielle (Ph.D. student), dbercoff@pasteur.fr

PLOQUIN Mickael (student), mploquin@pasteur.fr

SCHMITT Nathalie (Ph.D. student), nschmitt@pasteur.fr

SUDRY Hughes (student), hsudry@pasteur.fr

CANNOU Claude (Lab support), bcannou@pasteur.fr

DAVID Annie (Engineer), annied@pasteur.fr

JACQUEMOT Catherine (Technician)

NUGEYRE Marie-Therese (Engineer), mnugeyre@pasteur.fr

PROU-DELAIRE Marie-Claire (Lab support)

VERSMISSE Pierre (Technician), pversmis@pasteur.fr


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