Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

Abstract

Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-κB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-κB at 276th serine residue. These modifications enhance the interaction of NF-κB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication.

The effects of cocaine on HIV transcription

“…Several groups including ours have demonstrated that cocaine promotes both the activation of NF-κB and HIV replication [15, 73–76]. To extend those studies further, using monocytic cell lines (THP1 and U937) and primary monocytes derived macrophages (MDMs) [15], we found that during both acute (one time) and chronic (multiple time for 3 days) treatment, cocaine efficiently activates NF-κB.…”

“…The suboptimal penetration of HAART in the brain permits sustained low levels of viral replication and brain adaptive HIV evolution, which eventually contributes to the occasional systemic viral blips [11–14]. Moreover, recently we have proposed that owing to the lack of any transcriptional inhibitor, HAART regimens are unable to restrict HIV transcription [15]. Consequently, viral proteins are produced unchecked even in the presence of effective HAART [16].…”

“…In order to generate complete HIV genomic transcripts, transcription requires successful progression through both the initiation and elongation phases (Figure 1). In a recent publication, we have revealed some of the underlying molecular mechanisms that cocaine utilizes to promote both the initiation and elongation phases of HIV transcription in order to enhance the overall rate of HIV gene expression ( [15] Figure 2). …”

“…However very little is known about the involved molecular mechanisms that cocaine utilizes to enhance HIV gene expression. Recently, we have investigated some of the molecular mechanisms that are modulated by cocaine in order to enhance HIV transcription [15]. …”

“…To extend those studies further, using monocytic cell lines (THP1 and U937) and primary monocytes derived macrophages (MDMs) [15], we found that during both acute (one time) and chronic (multiple time for 3 days) treatment, cocaine efficiently activates NF-κB. Interestingly, cocaine not only promotes the activation (nuclear translocation) of NF-κB, but also enhances the functional activity of NF-κB by augmenting the ability of NF-κB to interact with histone acetyltransferases (HATs) (Detailed below and Figure 2).…”