Abstract
Human immunodeficiency virus type-1 (HIV-1) can either undergo a lytic pathway to cause productive systemic infections or enter a latent state in which the integrated provirus remains transcriptionally silent for decades. The ability to latently infect T-cells enables HIV-1 to establish persistent infections in resting memory CD4+ T-lymphocytes which become reactivated following the disruption or cessation of intensive drug therapy. The maintenance of viral latency occurs through epigenetic and non-epigenetic mechanisms. Epigenetic mechanisms of HIV latency regulation involve the deacetylation and methylation of histone proteins within nucleosome 1 (nuc-1) at the viral long terminal repeats (LTR) such that the inhibition of histone deacetyltransferase and histone lysine methyltransferase activities, respectively, reactivates HIV from latency. Non-epigenetic mechanisms involve the nuclear restriction of critical cellular transcription factors such as nuclear factor-kappa beta (NF-κB) or nuclear factor of activated T-cells (NFAT) which activate transcription from the viral LTR, limiting the nuclear levels of the viral transcription transactivator protein Tat and its cellular co-factor positive transcription elongation factor b (P-TEFb), which together regulate HIV transcriptional elongation. In this article, we review how T-cell receptor (TCR) activation efficiently induces NF-κB, NFAT, and activator protein 1 (AP-1) transcription factors through multiple signal pathways and how these factors efficiently regulate HIV LTR transcription through the non-epigenetic mechanism. We further discuss how elongation factor P-TEFb, induced through an extracellular signal-regulated kinase (ERK)-dependent mechanism, regulates HIV transcriptional elongation before new Tat is synthesized and the role of AP-1 in the modulation of HIV transcriptional elongation through functional synergy with NF-κB. Furthermore, we discuss how TCR signaling induces critical post-translational modifications of the cyclin-dependent kinase 9 (CDK9) subunit of P-TEFb which enhances interactions between P-TEFb and the viral Tat protein and the resultant enhancement of HIV transcriptional elongation.
Highlights
With the introduction of the highly active antiretroviral therapy (HAART), the morbidity and mortality rate among human immunodeficiency virus (HIV)-infected individuals has reduced dramatically [1]
The amount of latently infected cells is very limited, a highly stable pool of latently-infected cells are always present in HIV patients, which remains a barrier for human immunodeficiency virus type-1 (HIV-1) eradication in patients undergoing effective HAART therapy [12]
Roebuck and colleagues [69] reported that activator protein 1 (AP-1) binds to phorbol ester-responsive elements located within the 50 noncoding region of the HIV long terminal repeats (LTR) known as the downstream sequence element (DSE) located at nucleotide positions +84 to +105 and +149 to +170 to modulate Human immunodeficiency virus type-1 (HIV-1) transcription
Summary
With the introduction of the highly active antiretroviral therapy (HAART), the morbidity and mortality rate among HIV-infected individuals has reduced dramatically [1]. The ability of HIV to establish latent infections at the level of individual T-cells remains the main barrier to eradicate HIV [7]. The most-stable reservoir of HIV resides in the transcriptionally-silent resting memory CD4+ T-cells [9,10]. In transcriptionally-inert resting memory T-cells, HIV latency is established due to the unavailability of transcription factors [11]. The amount of latently infected cells is very limited (approximately one in one million of resting T-cells), a highly stable pool of latently-infected cells are always present in HIV patients, which remains a barrier for human immunodeficiency virus type-1 (HIV-1) eradication in patients undergoing effective HAART therapy [12]. We will shed light on post-translational modifications of the cyclin-dependent kinase 9 (CDK9) subunit of positive transcription elongation factor b (P-TEFb) which enhances the interactions between P-TEFb and the viral Tat protein and the resultant enhancement of HIV transcriptional elongation
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