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


  abstract

 

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

  • Study of the factors from the placental environment involved in the control of in utero HIV-1 Mother-to-Child Transmission (MTCT).

  • Control of HIV-1 replication and of survival of thymocytes upon infection within the thymus. Possibility of renewal of CD4 T cells by IL-7.

  • Early host determinants of protection against AIDS in African Green Monkeys

  • Factors of protection from HIV-1 infection.



  report

cale

I - Study of the factors from the placental environment involved in the control of in utero HIV-1 Mother to-Child Transmission (MTCT). Group leader : Elisabeth MENU

The placental environment is involved in the maintenance of pregnancy as well as in the natural protection of the fetus against in utero infections. We have shown a restriction at the level of the entry and/or at the early steps of the viral replication cycle when human placental trophoblast derived cells (cells in direct contact with maternal blood within the chorionic villi) are infected by cell free HIV1. In contrast, the contact with infected cells leads to the passage of HIV1 from the apical to the basolateral side in an in vitro model of a trophoblastic barrier reconstitution. This passage is modulated by the cytokines and chemokines which have shown to be present ex vivo in the placental environment. The mechanisms involved in both the increase and the blockage of the passage by these cellular factors are currently under investigation.

In collaboration with the Pasteur Center in Cameroon and the PHPT (Perinatal HIV Prevention Trial) group in Thailand, we are performing an ex vivo multicentric study to determine the effect on the placental environment of both HIV-1 infection and the antiretroviral treatments used to prevent MTCT. Different patterns are already observed for TNF alpha, IL-10 and SDF-1 in placentae from HIV-1 negative women and from HIV-1 positive women under multiple antiretroviral therapies (long term treatment). To understand the mechanisms by which antiretroviral drugs decrease in utero HIV-1 MTCT, we have established and validated an in vitro system of chorionic villi histocultures.

Overall, these studies are an essential step for the development and the evaluation of new antiretroviral molecules and with regard to future strategies using immunotherapy or vaccinotherapy in HIV-1 positive women.

II - Control of HIV-1 replication and of survival of thymocytes upon infection within the thymus. Possibility of renewal of CD4 T cells by IL-7. Group leader: Nicole ISRAEL.

The thymus is the organ of T cell renewal (thymopoïesis). However, this organ may be infected by HIV. We studied in which conditions the thymic microenvironment favor HIV replication in the thymus. Our first studies were performed in vitro, using a relevant system consisting in the coculture of human primary thymocytes with thymic stromal cells: the epithelial cells. Using this system, we have determined: i) the cytokines which favor HIV replication (TNF and IL-7), ii) the thymocyte subsets able to replicate the virus (the mature CD4+ and the immature intermediates), iii) the capacity of survival of these infected cells (the mature mature CD4+ thymocytes behave as a virus reservoir), iiii) the evolution of the tropism of the virus (from CCR5 à CXCR4) in the infected populations.

In addition, because of the role of IL-7, both in the thymopoïesis and in viral replication, we addressed the question whether this cytokine might favor CD4 T cell renewal without increasing the viral load in vivo. This was actually demonstrated in the SIV-infected macaque which was not under antiretroviral therapy. To definitively conclude on the interest of IL-7 as an immunorestorative therapy additive to antiretroviral treatment in AIDS, we studied the effect of IL-7 in the SIV-infected macaque under antiretroviral therapy.

We also started a study aiming at determining whether the infection of thymic dendritic cells might lead to modification(s) of the T cell repertoire.

III — Early host determinants of protection against AIDS in African Green Monkeys. Group leader: Michaela C. MULLER-TRUTWIN.

We are studying the infection by a simian lentivirus (SIV) in African Green monkeys (AGM) as a model for natural protection against AIDS, in collaboration with the Pasteur Institute in Dakar. Our previous data indicate a long presence of SIVagm in AGMs and a co-evolution of the virus and its host. We could demonstrate that the absence of pathology is not associated with the selection of viral variants attenuated for replication. We rather observed high levels of virus in the blood and also in the intestine from the early phase on of infection. Despite a persistent viremia, that reaches in some animals the same high levels as in HIV-1 infected humans progressing to AIDS, the viral load in the lymph nodes remains low and no signs of chronic activation of the lymphocytes could be observed. Similar data were obtained also in another natural host for SIV, the mandrill infected by SIVmnd. Early interactions between dendritic cells and T cells during the non-pathogenic SIVagm infection might be determinant for these profiles. We are therefore investigating the activation and maturation markers of dendritic cells and T lymphocytes induced by SIVagm infection in vivo. Furthermore, studies on the role of DC-SIGN in transmission of SIVagm to T cells and viral dissemination to lymph nodes are also ongoing.

IV - Factors of protection from HIV-1 infection. Group leader: Gianfranco PANCINO.

Some individuals repeatedly exposed to HIV-1 appear to be protected against HIV-1 (uninfected exposed individuals, EU). Our research aims to identify and characterize host factors involved in the resistance to HIV-1 infection. In collaboration with the Institutes Pasteur of the International Network, we are studying EU individuals systemically (intravascular drug users) or sexually (partners of seropositive individuals) exposed to HIV-1 in Vietnam, Cambodia and Central African Republic. The exposition to multiple infections possibly induces an immune activation in these populations. Activation of some immune compartments, in synergy or not with host genetic factors, may contribute to the protection against HIV-1 infection. We have observed a reduction of the susceptibility to in vitro infection by HIV-1 in some Vietnamese EU drug users. This reduction was associated either to intrinsic resistance of CD4+ cells or to viral suppression by CD8+ cells or both. Furthermore, we have also shown a significant increase of Natural Killer cell activity in Vietnamese EU. These data suggest that various mechanisms contribute to natural protection against HIV-1 in this population.

In parallel to EU studies, we have shown that the activation through FcgR of human macrophages induces a suppression of HIV-1 replication due, at least partially, to a block at the level of viral integration into the host genome.

Keywords: HIV/SIV, AIDS, Activation, Persistence, Control



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
  Magali JOULLIE (mjoullie@pasteur.fr) BARRE-SINOUSSI Françoise,fbarre@pasteur.fr

ISRAEL Nicole,nisrael@pasteur.fr

MENU Elisabeth,emenu@pasteur.fr

MULLER-TRUTWIN Michaela,mmuller@pasteur.fr

PANCINO Gianfranco,gpancino@pasteur.fr

SCOTT-ALGARA Daniel,scott@pasteur.fr

BEQ Stéphanie,sbeq@pasteur.fr

DERRIEN Muriel,mderrrien@pasteur.fr

DOLCINI Guillermina,guidol@pasteur.fr

PLOQUI Mickael,mploquin@pasteur.fr

SCHMITT Nathalie,nschmitt@pasteur.fr

AILLET Fabienne (Technicienne supérieure IP), fja1@pasteur.fr

CANNOU Claude (Aide de laboratoire, IP),bcannou@pasteur.fr

DAVID Annie (Ingénieur IP),annied@pasteur.fr

NUGEYRE Marie-Thérèse (Ingénieur IP),mnugeyre@pasteur.fr

PROU-DELAIRE Marie-Claire (Agent de laboratoire, IP)

VERSMISSE Pierre (Technicien supérieur IP),pversmis@pasteur.fr

Activity Reports 2002 - Institut Pasteur
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