%0 Journal Article
%T Cellular Cofactors of Lentiviral Integrase: From Target Validation to Drug Discovery
%A Oliver Taltynov
%A Belete A. Desimmie
%A Jonas Demeulemeester
%A Frauke Christ
%A Zeger Debyser
%J Molecular Biology International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/863405
%X To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs). 1. Introduction: Cofactors of Integration as Potential Antiviral Targets Infection with the human immunodeficiency virus type 1 (HIV-1) remains a substantial public health as well as a socioeconomic problem worldwide [1]. Although highly active antiretroviral therapy (HAART) effectively halts HIV replication and profoundly increases survival of patients, it has not been possible yet to achieve a cure. Interruption of HAART typically results in a rebound of virus replication. This is primarily due to the fact that HIV has evolved mechanisms to escape from the continuous immune surveillance in a small pool of latently infected cells that are not susceptible to drug therapy. These latently infected cells reside in reservoirs where the distribution of antiretroviral (ARV) drugs is extremely variable and often lower than the expected maximal inhibitory concentration (for recent reviews see [2¨C4]). Moreover, the rapid replication rate and the generation of an extensive genetic diversity fuel the emergence of drug-resistant viral strains resulting in treatment failure [5, 6]. Therefore, there is a continuous demand to search for novel and better ARVs for a better control of the HIV pandemic with the hope to eventually induce permanent remission of the disease. HIV relies
%U http://www.hindawi.com/journals/mbi/2012/863405/