I/ Control of HIV-1 transmission in utero : a model to study the regulation of the passage of the virus across a cellular barrier. Responsable:Elisabeth Menu.
In a reconstitution model of a placental barrier in vitro, two mechanisms resulting in a preferential passage of maternal viral quasi-species have been identified as a consequence of the interaction of trophoblast with HIV1infected cells: a cellular fusion leading to a selection of X4 viruses and a rapid transport of maternal viral variants across the trophoblast barrier by transcytosis. In contrast, there is no transmission of HIV1 when trophoblast cells are exposed to cell free virus, mostly because of a restriction at the level of viral entry. Investigations in vitro and ex vivo on further regulations of HIV1 within the placental microenvironment are currently ongoing. These studies, launched together with an international network of collaborations are focusing on the impact of soluble placental factors (cytokines and chemokines) and of cell surface molecules (HIV-1 co-receptors, HLA-G and adhesion molecules).
II/ Control of HIV-1 replication and of survival of thymocytes upon infection within the thymus. Responsable: 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 crucial cytokines for viral replication, namely TNF and IL-7, which further synergize with IL-6, IL-1 and GM-CSF. However this interaction is efficient only with mature CD4+thymocytes. In the other CD4+ thymocytes, viral replication is restricted either by their unresponsiveness to cytokines ( double-positive cells) or by a lack of TNF secretion (intermediate thymocyte population). However, in the latter, 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. Altogether these data suggest that in vivo, HIV infection might create a persistent virus reservoir 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. Responsable: Michaela MÜLLER-TRUTWIN
African green monkeys (AGM) are the biggest reservoir of primate lentivirus (SIV) in natura. They remain asymptomatic when infected and are thus good models to study natural protection against AIDS. The lack of AIDS in these monkeys is not related to mutations in the coding regions for the CD4 and CCR5 receptors. Acutely and chronically SIVagm infected monkeys display a high viremia similar to humans infected by HIV-1 and thus, their virus (SIVagm) is not attenuated. Despite a persistent replication in AGMs, no follicular hyperplasia and disorganization of the follicular dendritic cell network, nor infiltration of CD8+ cells into the germinal centers of the lymph nodes are observed. Differences in early immune cell activation in the host might explain the distinct pattern of disease evolution in AGM and in humans infected by SIVagm and HIV, respectively.
IV/ Determinants of natural protection against HIV-1 infection in human. Responsable: Gianfranco PANCINO
Host determinants of protection against HIV-1 infection are studied with a particular attention to the role of immune activation. Two complementary studies are on going. The first one aim to identify immune markers related to the natural protection against HIV-1 infection observed in seronegative individuals at high risk of infection in Africa and Asia. The second one consists in the analysis of modulations of HIV-1 infection in activated macrophages. Three cohorts of exposed uninfected (EU) individuals (intravenous drug users and partners of HIV-infected individuals) have been established, in collaboration with the Pasteur Institutes in Ho Chi Minh City, Phnom Penh and Bangui. Immune activation markers, cell susceptibility to HIV-1 infection ex vivo as well as, in collaboration with D. Scott-Algara, NK cell activity are studied in EUs with regard to non infected control population. The relationship between macrophage activation and protection against HIV-1 is addressed by studying the impact of naturally occurring stimuli on HIV-1 infection in macrophages in vitro. This study clearly shows that HIV-1 replication is suppressed in macrophages activated via the Fc receptors for IgG (FcgR).