Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription

Abstract

Polyomavirus JC (JCV) is the aetiological agent of progressive multifocal leukoencephalopathy (PML), a frequently fatal infection of the brain afflicting nearly 4 % of AIDS patients in the USA. Human immunodeficiency virus type 1 (HIV-1) Tat, acting together with cellular proteins at the JCV non-coding control region (NCCR), can stimulate JCV DNA transcription and replication. Tat in the brain is secreted by HIV-1-infected cells and incorporated by oligodendroglia, cells capable of infection by JCV. Thus far the effects of Tat on JCV have been studied primarily with protein encoded by the HIV-1 B clade most common in North America. Here, we determine the abilities of Tat from different HIV-1 clades to alter JCV early and late gene transcription and DNA replication initiated at the JCV origin. Tat from all clades tested stimulates both JCV early and late gene promoters, with clade B Tat being significantly most effective. Tat proteins from the HIV-1 clades display parallel patterns of differences in their effects on HIV-1 and JCV transcription, suggesting that Tat effects in both cases are mediated by the same cellular proteins. Clade B Tat is most effective at directing Smad mediators of tumour growth factor beta and cellular partner Pura to the NCCR. Tat proteins from all non-B clades inhibit initiation of JCV DNA replication. The effectiveness of HIV-1 clade B Tat at promoting JCV transcriptional and replicative processes highlights a need for further investigation to determine which molecular aspects of Tat from distinct HIV-1 substrains can contribute to the course of PML development in neuroAIDS.

Oligodendrocyte Injury and Pathogenesis of HIV-1-Associated Neurocognitive Disorders

“…In HIV-1 patients with PML complication, Tat and JCV both are present in oligodendrocytes. Tat has been shown to synergize with JCV, and facilitate of JCV gene transcription and replication, leading to robust JCV infection [ 37 , 38 ]. Tat stimulates JCV gene transcription by cooperating with SMAD proteins, the intracellular effectors of TGF-beta, at the JCV DNA control region [ 37 ].…”

“…Tat stimulates JCV gene transcription by cooperating with SMAD proteins, the intracellular effectors of TGF-beta, at the JCV DNA control region [ 37 ]. The effectiveness of Tat on facilitating JCV transcription and replication varies from different HIV-1 clades [ 38 ]. Since Tat is expressed in the brain at relative high levels while the viral load is controlled in blood, this may, at least in part, explain why some HIV-1 patients still develop PML despite having a good access to cART [ 39 ].…”

HIV-associated progressive multifocal leukoencephalopathy: current perspectives

“…[45][46][47] Notably, Tat enhances the ability of Pur-α 48 to bind the up-TAR element in the JCV-NCCR region, thus synergistically activating transcription 49 and contributing to PML pathogenesis during HIV infection. Despite HIV and JCV infecting different cell types, Tat protein is secreted by HIV-infected cells, such as microglial cells, astrocytes, and monocytes, and can be internalized by JCV-infected oligodendrocytes, 50 contributing to the enhancement of viral replication and transcription. 49 Concerning the different HIV-1 clades and JCV interactions, HIV-1 clade B-associated Tat protein was found to be more effective in activating JCV early and late gene transcription in glial cells, than Tat from other clades, in vitro.…”

“…49 Concerning the different HIV-1 clades and JCV interactions, HIV-1 clade B-associated Tat protein was found to be more effective in activating JCV early and late gene transcription in glial cells, than Tat from other clades, in vitro. 50 Immune deficiency and JCV reactivation: immune pathogenesis of PML The PML pathogenesis is still not completely clarified, since the source of the primary infection, the site of viral latency, and the route by which JCV enters into the brain have not been exactly understood. However, the conditions facilitating JCV-induced PML onset are well known: 1) changes in the NCCR with enhancement of viral transcription and replication, 2) availability of transcription factors binding the rearranged NCCR, 3) immunodeficiency, and 4) individual genetic predisposition.…”

Neurobehavioral Manifestations of Human Immunodeficiency Virus/AIDS

“…Under conditions of immunosuppression, including HIV infection, JCV can reactivate and cause PML. HIV+ patients are doubly at risk, as JCV replication can also be increased by the HIV tat protein 106 .…”