Macrophages as HIV-1 reservoir
Abstract
Macrophages as HIV-1 reservoir Infection with human immunodeficiency virus type 1 (HIV-1) causes one of the most devastating illnesses of the human being, the acquired immunodeficiency syndrome (AIDS). Since its discovery more than 64.9 million people have been infected with HIV world-wide, with more than 32 million AIDS-related deaths. As a major accomplishment in HIV/AIDS medicine, the introduction of highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of HIV-infected persons. Under therapy a significant proportion of treated individuals reach a level close to a normal life expectancy. However; the virus can persist in the body in spite of the presence of drugs that successfully inhibit key steps in the virus life cycle. It is well known that HIV remains detectable in latently infected CD4+ T lymphocytes and cells of the macrophage-monocyte lineage. Therefore, these cells constitute the viral reservoir. Monocyte-derived macrophages (MDM) are widely distributed in all tissues and organs, including the central nervous system, where they represent the most common HIV-infected cells. In contrast to activated CD4+ T lymphocytes, MDM are resistant to cytopathic effects and survive HIV infection for a long period of time. The molecular mechanisms of how HIV is able to persist in macrophages are not fully elucidated yet. In this context, we will study the effect of in vitro HIV-1 infection on parameters related with cell damage, repair and death in MDM. We found in preliminary results that in vitro infection with HIV-1 induces telomerase activity. Therefore, we will further investigate if this results in increasing telomere length in MDM, as well as if cell proliferation and life span in MDM is affected. Secondly, the cellular damage status of MDM after infection will be determined using some key parameters like DNA damage and repair capacity, apoptosis rate, reactive oxygen species (ROS) content and the cell response to oxidative stress. Finally, we propose to compare these in vitro results with ex vivo ones analysing all parameters mentioned above in monocyte-derived macrophages from HIV-infected individuals. Consequently, the proposed experiments will help to elucidate if HIV-1 is able to regulate cellular parameters connected with cellular stress and survival. Our results will throw light on what viral mechanisms are involved in HIV persistence in macrophages and thus might contribute to the discovery of novel molecular targets for therapeutic strategies targeting the viral reservoirs.
Publikationen
Project staff
Regina Grillari
Assoc. Prof. Dr. Regina Grillari
regina.grillari@boku.ac.at
Project Leader
01.10.2010 - 30.09.2013