HIV remains incurable due to the existence of a reservoir of cells that harbor intact integrated genomes of the virus in the absence of viral replication. This population of infected cells remains invisible to the immune system and is not targeted by the drugs used in the current antiretroviral therapies (cART). Reversal of latency by the use of inhibitors of chromatin-remodeling enzymes has been studied extensively in an attempt to purge this reservoir of latent HIV but has thus far not shown any success in clinical trials. The full complexity of latent HIV infection has still not been appreciated, and the gaps in knowledge prevent development of adequate small-molecule compounds that can effectively perturb this reservoir. In this review, we will examine the role of epigenetic silencing of HIV transcription, posttranscriptional regulation, and mRNA processing in promoting HIV-1 latency.
BackgroundDifferent classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing.ResultsHere we show that various lysine and arginine mutations reduce the capacity of Tat to induce both transcription and mRNA splicing. The lysine 28 and lysine 50 residues of Tat, or the acetylation and methylation modifications of these basic amino acids, were essential for Tat transcriptional control, and also for the proviral expression effects elicited by histone deacetylase inhibitors (HDACi) or the bromodomain inhibitor JQ1. We also found that JQ1 was the only LRA tested that could induce HIV mRNA splicing in the absence of Tat, or rescue splicing for Tat lysine mutants in a BRD4-dependent manner.ConclusionsOur data provide evidence that Tat activities in both co-transcriptional RNA processing together with transcriptional initiation and processivity are crucial during reactivation of latent HIV infection. The HDACi and JQ1 LRAs act with Tat to increase transcription, but JQ1 also enables post-transcriptional mRNA splicing. Tat residues K28 and K50, or their modifications through acetylation or methylation, are critical for LRAs that function in conjunction with Tat.Electronic supplementary materialThe online version of this article (10.1186/s12977-018-0421-6) contains supplementary material, which is available to authorized users.
Background The burden of Parkinson’s disease (PD) worsens with disease progression. However, the lack of objective and uniform disease classification challenges our understanding of the incremental burden in patients with advanced Parkinson’s disease (APD) and suboptimal medication control. The 5–2-1 criteria was proposed by clinical consensus to identify patients with advancing PD. Our objective was to evaluate the screening accuracy and incremental clinical burden, healthcare resource utilization (HCRU), and humanistic burden in PD patients meeting the 5–2-1 screening criteria. Methods Data were drawn from the Adelphi Parkinson’s Disease Specific Program (DSP™), a multi-country point-in-time survey (2017–2020). People with PD who were naive to device-aided therapy and on oral PD therapy were included. Patients meeting the 5–2-1 screening criteria had one or more of the three clinical indicators of APD: (i) ≥5 doses of oral levodopa/day, OR (ii) “off” symptoms for ≥2 h of waking day, OR (iii) ≥1 h of troublesome dyskinesia. Clinician assessment of PD stage was used as the reference in this study. Clinical screening accuracy of the 5–2-1 criteria was assessed using area under the curve and multivariable logistic regression models. Incremental clinical, HCRU, and humanistic burden were assessed by known-group comparisons between 5 and 2-1-positive and negative patients. Results From the analytic sample (n = 4714), 33% of patients met the 5–2-1 screening criteria. Among physician-classified APD patients, 78.6% were 5–2-1 positive. Concordance between clinician judgment and 5–2-1 screening criteria was > 75%. 5–2-1-positive patients were nearly 7-times more likely to be classified as APD by physician judgment. Compared with the 5–2-1-negative group, 5–2-1-positive patients had significantly higher clinical, HCRU, and humanistic burden across all measures. In particular, 5–2-1-positive patients had 3.8-times more falls, 3.6-times higher annual hospitalization rate, and 3.4-times greater dissatisfaction with PD treatment. 5–2-1-positive patients also had significantly lower quality of life and worse caregiver burden. Conclusions 5–2-1 criteria demonstrated potential as a screening tool for identifying people with APD with considerable clinical, humanistic, and HCRU burden. The 5–2-1 screening criteria is an objective and reliable tool that may aid the timely identification and treatment optimization of patients inadequately controlled on oral PD medications.
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