LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20 |
| |
| Authors: | Mélanie R. Tardif Caroline Gilbert Sandra Thibault Jean-Fran?ois Fortin Michel J. Tremblay |
| |
| Affiliation: | Centre de Recherche en Infectiologie,1. Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier de l''Université Laval, Faculté de Médecine, Université Laval, Québec, Canada,2. Boehringer-Ingelheim, Laval, Québec, Canada3. |
| |
| Abstract: | Adhesion molecules are known to play major roles in the initiation and stabilization of cell-to-cell contacts during the immunological response. Human immunodeficiency virus type 1 (HIV-1) exploits those interactions to facilitate infection and propagation processes. The primary objective of the present study was to investigate the ability of antagonists specific for lymphocyte function-associated antigen 1 (LFA-1) to diminish HIV-1 infection and transmission. We demonstrate here that LFA-1 antagonists can significantly reduce HIV-1 replication in primary human cells and virus propagation by affecting cell-to-cell interactions. Moreover, the inhibition of LFA-1-mediated adhesion events also potentiates the antiviral efficacy of the peptide fusion inhibitor T-20. Altogether, our data suggest that LFA-1 antagonists represent promising antiviral agents. Antiadhesion therapy could be considered a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.Actual strategies to treat human immunodeficiency virus type 1 (HIV-1)-infected individuals make use of highly active antiretroviral therapy. It has been demonstrated that it reduces viral load, improves survival time, and decreases AIDS-associated mortality. Unfortunately, highly active antiretroviral therapy presents numerous severe drawbacks including the emergence of resistant strains, cross-resistance to other drugs within the same class, transmission of drug-resistant strains, extensive and adverse side effects for patients under treatment, and considerable costs. Therefore, the development of alternative therapeutic approaches aimed at novel targets is urgently needed.The present work focuses on the membrane glycoprotein lymphocyte function-associated antigen 1 (LFA-1), an integrin playing crucial roles in leukocyte trafficking, inflammation, and the orchestration of the immune response. Interactions between LFA-1 and its counterreceptors, called intercellular adhesion molecules (ICAMs), initiate the immune response by strengthening the adhesion between antigen-presenting cells (APCs), such as dendritic cells (DCs), macrophages, or B cells, and CD4+ T lymphocytes through the formation of the immunological synapse and by participating in leukocyte migration toward inflamed tissues or secondary lymphoid organs. LFA-1 is a heterodimeric receptor constituted of CD11a (α chain) and CD18 (β chain). LFA-1-mediated adhesion is regulated by conformational changes (affinity), lateral diffusion, and the spatial organization (avidity) of this integrin within the plasma membrane (19, 36, 54, 55, 61).Cell-to-cell transmission is the most rapid and potent mechanism by which HIV-1 can infect CD4+ T cells (12). Indeed, the virus takes advantage of the normal communication between immune cells for its own propagation. A virological synapse (VS) is formed by the recruitment of multiple HIV-1 receptors and coreceptors, virus-encoded gp120 and gp41, adhesion molecules, and cytoskeleton elements at the interface of HIV-1 donor and target cells, thus favoring the directed budding and fusion of newly synthesized virions. The VS can be created between infected and uninfected CD4+ T cells (34, 44) as well as between DCs or other carrier cells exposed to viral particles and target T cells (1, 2, 7, 16, 59). VS formation relies on LFA-1-mediated adhesion via ICAMs, particularly ICAM-1 and ICAM-3 (4, 30, 31, 33, 35, 51). It has been demonstrated that interactions of LFA-1 and ICAM-1 can modulate HIV-1 transfer from immature DCs (iDCs) to CD4+ T cells (51). Moreover, the importance of interactions between LFA-1 and ICAM-1 in HIV-1 transmission has been confirmed using T cells from leukocyte adhesion deficiency type 1 patients (30). Furthermore, interactions between LFA-1 and ICAMs play relevant roles in cell-free HIV-1 infection. Virions are efficiently released by infected cells in the external environment, and even though free viruses have a short life span (25), a number of them can bind and productively infect target cells. The efficiency of this mode of infection is strongly increased by the incorporation of certain host molecules into the viral envelope. Indeed, it was previously shown that the insertion of host-derived ICAM-1 within HIV-1 particles significantly increases the infection process of primary human CD4+ T cells expressing cell surface LFA-1 molecules (21-23, 56).Immune hyperactivation is an important feature of HIV-1 pathogenesis during the chronic phase of infection. Chronically infected individuals share multiple immune abnormalities, including a rapid turnover of CD4+ T cells, T-cell depletion, polyclonal B-cell activation, destruction of the architecture of some secondary lymphoid tissues, and immunodeficiency. A number of these clinical manifestations share similarities with the ones observed for allergic and autoimmune diseases. Interestingly, some of those conditions are currently being treated with agents that can block interactions between LFA-1 and ICAM-1 (13, 14, 29, 32).Given the involvement of LFA-1 in different important physiological processes, the pharmaceutical industry has devoted great efforts to the development of potent antagonists over the past decade, with the aim of treating cancer as well as multiple inflammatory and autoimmune diseases. Consequently, various classes of LFA-1 inhibitors have been tested, which has allowed the highlighting of the complex mechanism of action of this integrin in various processes such as rolling, migration, and firm adhesion. Among those compounds, statins such as lovastatin and other molecules like XVA143 have been demonstrated to antagonize LFA-1-mediated cellular adhesion in different manners. For instance, lovastatin restrains the association between LFA-1 and ICAM-1 and impairs LFA-1-mediated immune functions such as homotypic adhesion, rolling, and transmigration in addition to inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (49). Likewise, in the presence of XVA143, ICAM-1 interactions are not strong enough to allow firm attachment (52, 53), but an increase of the rolling of the immune cells on the endothelium is still observed (49).It was previously reported that lovastatin inhibits the infection of CD4+ T cells by cell-free ICAM-1-bearing HIV-1 (26, 28). Moreover, lovastatin was also found to reduce viral load and increase CD4+ T-cell counts in chronically HIV-1-infected patients (15). Therefore, in an attempt to provide additional information on the efficacy of LFA-1 antagonists in limiting virus infection and propagation, we tested the capacity of XVA143 and lovastatin to modulate HIV-1 infection in monocultures enriched in activated CD4+ T cells and in cocultures containing iDCs and autologous CD4+ T cells. In addition, to investigate whether LFA-1 antagonists could help antiretroviral compounds prevent virus infection, experiments using T-20 in combination with LFA-1 antagonists were also performed. |
| |
| Keywords: | |
|
|
