Unit: Retrovirus Biology

Director: Françoise BARRE-SINOUSSI

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

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

Infection of the thymus by VIH-1 :its impact on thymopoïesis and CD4 lymphopenia; study of CD4 T cell renewal by an immunotherapy using Interleukin 7 (IL7).

Early host determinants of protection against AIDS in African Green Monkeys

Factors of protection from HIV-1 infection.

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 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 HIV-1. In contrast, a productive infection might be induced by pro-inflammatory cytokines (such as TNF or IL-1) enhanced by parasitic infections for example. We are currently investigating this hypothesis in an in vitro system of chorionic villi histocultures that we have established and validated in our laboratory. The contact with infected cells leads to the passage of HIV-1 from the apical to the basolateral side, in an in vitro model of a trophoblastic barrier reconstitution. The cytokines and chemokines that we have shown to be present ex vivo in the placental environment modulate this passage. 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 " Centre Pasteur " of Cameroon and the PHPT (Perinatal HIV Prevention Trial) group in Thailand, we are performing an ex vivo multicentric study to determine the effect of both HIV-1 infection and the antiretroviral treatments used to prevent MTCT on the placental environment. Different patterns are observed according to the studied groups. Clinical, biological and pharmaceutical parameters are collected and will be taken into account for the final analysis of the data. In parallel, the impact of HIV-1 and of antiretroviral drugs on the placental environment is directly tested on chorionic villi histocultures.

Overall, these studies should improve our understanding of the various parameters involved in the control of HIV-1 MTCT and the development and the evaluation of new strategies to prevent HIV-1 MTCT.

II - Infection of the thymus by VIH-1: impact on thymopoïesis and CD4 lymphopenia. CD4 T cell renewal by immunotherapy using Interleukin 7. Group leader: Nicole ISRAEL.

HIV-1 may infect the thymus, which is the organ of T cell renewal (thymopoïesis). 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: 1) the cytokines which favor HIV replication (TNF and IL-7); 2) the thymocyte subsets able to replicate the virus (the mature CD4+ and the immature intermediates); 3) the capacity of survival of these infected cells (the mature CD4+ thymocytes behave as a virus reservoir); 4) 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 SIV-infected macaques, in absence of antiretroviral treatment. To definitively conclude on the interest of IL-7 as an immunotherapy in combination with antiretroviral drugs to improve T cell renewal, we studied the effect of IL-7 in SIV-infected macaques under antiretroviral treatment.

Our work also aims 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 Institut Pasteur in Dakar, Senegal. Our previous data on the SIVagm subtypes and co- and trans-receptors of SIVagm indicate a long presence of SIVagm in AGMs and a co-evolution of the virus and its host. We demonstrated 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 in the intestine from the early phase on of infection. Despite a persistent viremia, that often reaches 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 T lymphocytes are observed. Similar data were also obtained 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 profiles of dendritic cells and T lymphocytes induced by SIVagm infection in vivo. Furthermore, functional studies on these cells are ongoing.

IV - Factors of natural resistance to HIV-1 infection. Group leader: Gianfranco PANCINO.

The susceptibility to HIV-1 infection is highly variable among individuals. Some individuals repeatedly exposed to HIV-1 seem to be resistant to infection (exposed uninfected, EU). Our researches aim to identify and characterize the host factors involved in the resistance to HIV-1 infection, focusing on innate immunity mechanisms. In collaboration with the International Network of the Institut Pasteur, we studied systemically exposed (intravenous drug users, IDU) or sexually exposed (partners of seropositive individuals) EUs in Vietnam, Cambodia and Central African Republic. Distinct factors seem to contribute to the natural resistance to HIV-1 infection in these populations. We especially observed a decreased susceptibility of peripheral mononuclear cells from some EUs to HIV infection, which is indeed related either to an intrinsic resistance of their CD4+ cells to infection or to an inhibitory activity of their CD8+ cells. A highly significant increase of the cytotoxic and secretory activities of their Natural Killer cells has been also detected in IDU EUs, in collaboration with D. Scott-Algara. These results suggest that the activation of innate immunity compartments, possibly in synergy with predisposition factors, may contribute to the protection against HIV-1 infection. Investigations on the role of NK cell, in particular an analysis of the NK repertoire in EUs are currently ongoing, in collaboration with D. Scott-Algara in our lab and with P. Paul and E.Vivier in Marseilles. We are also focusing our attention on the mechanisms by which HIV-1 replication is restricted in target cells (CD4+ T cells and macrophages). In an in vitro model of primary macrophage infection, we have shown that FcR gamma stimulation, mimicking the stimulation by immune complexes, causes the suppression of HIV-1 replication. Viral suppression is due to a restriction of viral integration into the host genome. The mechanisms underlying the inhibition of viral integration are currently under investigations.

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

Activity Reports 2003 - Institut Pasteur

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