Unit: Retrovirus Biology
Director: Françoise BARRE-SINOUSSI
Our Unit is conducting research on factors involved in regulations of HIV/SIV infections within the host and/or host tissues:
Regulation of HIV-1 infection at the level of a cellular barrier: the placenta
Regulation of HIV-1 replication and of the survival of infected thymocytes within the thymic environment
Early host determinants of protection against AIDS in African Green Monkeys (AGM)
Determinants of innate resistance to HIV-1 infection in humans
Regulation of HIV-1 infection by innate immunity.
I - Regulation of HIV-1 infection at the level of the placenta barrier. Group leader: Elisabeth MENU
Our studies aim to investigate the mechanisms involved in the efficient control of in utero mother-to-child transmission (MTCT) of HIV-1. We have shown that the placental trophoblast cells are not permissive to the infection by cell-free virions, because of a restriction occurring at the early steps of the viral replication cycle before viral integration. This restriction has been confirmed at the level of placental tissues, in the absence of exogenous activation. We are actually studying the factors and mechanisms involved in this restriction. We have also shown that the passage of the virus through the trophoblast barrier, resulting from cell-to-cell contacts, is regulated by cytokines of the placental environment. The increase of the expression of placental pro-inflammatory cytokines that we observed in a multi-centric study involving the " Centre Pasteur " of Cameroon and the PHPT (Perinatal HIV Prevention Trial) group in Thailand, might explain the additional risk of MTCT during co-infections. The efficiency of MTCT preventive antiretroviral therapy might be, at least partially, explained by their impact on placental cytokine expression that we are currently studying ex vivo.
Overall, this work should contribute to a better understanding of parameters implicated in innate and/or therapeutic control of HIV-1 MTCT and, consequently, to the development and evaluation of new preventive strategies of HIV-1 MTCT. Indeed, using our tools and models in vitro, we are already investigating the efficiency of entry and fusion inhibitors to block cell-to-cell infection at the level of the placental barrier.
II - Regulation of HIV-1 replication and of the survival of infected thymocytes within the thymic environment. Group leader: Nicole ISRAEL.
Defects in both intrathymic and extrathymic pathways have been proposed to explain the progressive decline of CD4+ T cells in HIV-1 infection. Our study aims to identify mechanisms that impact HIV-1 infection and survival of infected cells within the thymic environment. We demonstrated that 1) two cytokines of the environment (IL-7 and TNF) are critical for HIV-1 replication and survival of thymic target cells in vitro; 2) IL-7 favors X4 HIV-1 replication over R5 viruses in mature thymocytes and protects them from apoptosis; 3) immature thymocytes might also participate to the viral spreading in the context of an inflammatory TNF response, but they remain sensitive to virus-induced apoptosis, and consequently, their infection might contribute to a defect in T cell renewal. According to these data, we raised the question of benefit versus adverse effects of IL7 therapy in SIV infected macaques in vivo, treated or not with antiretroviral (ARV) drugs. We provided evidences that, despite its impact on X4 replication and survival of infected mature thymocytes, IL-7 treatment might be beneficial for T cell recovery in patients under ARV therapy, through both T cell expansion and thymic output. We are now investigating if : 1) the presence of X4 HIV-1 in thymic emigrants, as a marker of a thymic infection, might be predictive of the immunological failure observed in few patients under ARV therapy; 2) thymic dendritic cells are permissive or not to HIV-1 with preliminary data indicating a preferential tropism of these cells for R5 viruses and 3) the infection of thymic DC is inducing dysregulations of their functions, in particular in terms of negative selection of T cells.
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. Our previous data on the SIVagm subtypes and their co- and trans-receptors 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 related to a selection of viral variants attenuated for replication. We rather observed high levels of virus in plasma as well as in intestinal tissues. Despite a persistent viremia to similar levels as in HIV-1 infected humans progressing to AIDS, no signs of chronic activation of lymphocytes are observed in AGMs. Early interactions between dendritic cells and T cells might be a key determinant for this activation profile. We are presently investigating the activation and maturation profiles of dendritic cells and of T lymphocytes induced by SIVagm infection in vivo. These studies are conducted using classical (flow cytometry...) and global (microarray) approaches.
IV - Determinants of innate resistance to HIV-1 infection in humans. Group leader: Gianfranco PANCINO.
Our researches aim to identify host factors involved in innate restriction to HIV-1 infection: 1) by studying the mechanisms of resistance in individuals who, despite repeated exposures to HIV-1, do not show any sign of infection (exposed uninfected, EU); 2) by using a model of restriction of HIV-1 replication in primary macrophages. Our data on EU exposed as intravenous drug users (IDU) or as partners of HIV-1+ individuals, in collaboration with the Instituts Pasteur of Ho Chi Minh City (Vietnam), Cambodia and Bangui (CAR) indicate that multiple factors, including innate mechanisms of defense, contribute to their resistance to HIV-1 infection. A decreased susceptibility of CD4 T cells to infection by HIV-1 and/or an inhibitory activity of CD8 T cells were observed more frequently in EUs than in controls. We also evidenced an increased cytotoxic and secretory NK cell activities in Vietnamese IDU EUs. In our in vitro model, we demonstrated that the activation of primary macrophages through FcγR, mimicking the stimulation by immune complexes, is suppressing HIV-1 replication by inhibiting viral integration into the host genome. We are currently investigating the mechanisms of restriction in CD4 T cells as well as in activated macrophages. Three phenotypes of restriction affecting early steps of HIV-1 replication cycle in CD4 T cells have already been identified. In some but not all cases, the restriction to R5 HIV-1 infection is associated to new CCR5 mutations.
V - Regulation of HIV infection by Innate Immunity. Group leader: Daniel SCOTT-ALGARA.
Our investigations on the role of the innate immunity, in particularly NK cells, in the control of HIV infection are conducted in collaboration with G.Pancino and the Institut Pasteur of Ho Chi Minh city. According to our previous observations of an enhanced NK cell activities in Vietnamese IDU EUs, we are now studying the level of expression of NK cell receptors and ligands, using flow cytometry analysis and real time PCR (in collaboration with P. Paul, Marseilles). Our preliminary data already suggest a selective expansion of NK cell subsets bearing activating and inhibitory receptors in EUs, which may represent an advantage for NK cells to control the infection and/or disease progression. We will now further study the role of NK cell subsets, in particular their cross talk with dendritic cells and/or macrophages exposed or not to HIV-1, according to their own implication in HIV-1 spreading in vivo.
Keywords: HIV/SIV, AIDS, Pathogenesis, Innate regulations, T cell homeostasis