Conservation of the Nuclear Receptor Response Element in HIV-1 LTRs: A Possible PPAR Response Element?

Infection with HIV-1 continues to be a threat to public health. Successful antiretroviral therapy has reduced the risk of developing AIDS but cannot fully eradicate the virus due to latent proviral sequences remaining in infected cells. The 5′-long terminal repeat (LTR) of HIV-1 is critical for the regulation of transcription of the viral RNA and subsequent production of new viral particles. Indeed, the regulation of transcription relies upon the binding of host cell transcription factors and associated regulatory proteins to the LTR. Recently, it has been found that the treatment of cells with ligands of a number of nuclear receptors (NRs) resulted in inhibition of HIV-1 replication. This inhibition likely occurs via effects on other proteins that bind to the 5′-LTR, notably NF-κB. Here, the possible binding site of one NR, the peroxisome proliferator-activated receptor (PPAR), in the HIV-1 5′-LTR is analysed within isolates of the virus. Given the high mutation rate of HIV-1, it is striking that this region remains conserved in more recent isolates from geographically distinct regions. This work provides a rationale for further study of the binding site recognised by PPAR in the HIV-1 5′-LTR. 1. Introduction The human immunodeficiency virus (HIV-1) remains a major threat to human health in many parts of the world although the incidence of AIDS has declined due to the development of antiretroviral therapy [1]. Advances in treatments have emerged from knowledge of how the virus replicates within host cells. Following infection, the RNA genome of HIV-1 is reverse transcribed and integrated into the host chromosomes as a provirus. The genome structure of HIV-1 includes 5′- and 3′-long terminal repeats (LTRs), as well as coding sequences for viral proteins (Figure 1(a)). The replication of HIV-1 is controlled by cellular proteins that bind to the 5′-LTR of the integrated provirus [2, 3], as well as to downstream regulatory elements within the virus protein coding sequence [4]. One important class of proteins that interact with the 5′-LTR is the nuclear receptor (NR) superfamily, members of which bind to a specific response element termed NRRE-1-DE (Figure 1(b)) [5]. In particular, the heterodimer formed of the peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) was able to induce the LTR reporter gene in the presence of the ligands clofibric acid and 9-cis-retinoic acid, respectively [5]. Figure 1: The location of the NRRE-1-DE in the HIV-1 5′-LTR. (a) The HIV-1 genome has a 5′-LTR, protein coding sequences ( gag, pol, vif, vpr,