Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage

Human immunodeficiency virus type 1 (HIV-1) has been shown to replicate productively in cells of the monocyte-macrophage lineage, although replication occurs to a lesser extent than in infected T cells. As cells of the monocyte-macrophage lineage become differentiated and activated and subsequently travel to a variety of end organs, they become a source of infectious virus and secreted viral proteins and cellular products that likely initiate pathological consequences in a number of organ systems. During this process, alterations in a number of signaling pathways, including the level and functional properties of many cellular transcription factors, alter the course of HIV-1 long terminal repeat (LTR)-directed gene expression. This process ultimately results in events that contribute to the pathogenesis of HIV-1 infection. First, increased transcription leads to the upregulation of infectious virus production, and the increased production of viral proteins (gp120, Tat, Nef, and Vpr), which have additional activities as extracellular proteins. Increased viral production and the presence of toxic proteins lead to enhanced deregulation of cellular functions increasing the production of toxic cellular proteins and metabolites and the resulting organ-specific pathologic consequences such as neuroAIDS. This article reviews the structural and functional features of the cis-acting elements upstream and downstream of the transcriptional start site in the retroviral LTR. It also includes a discussion of the regulation of the retroviral LTR in the monocyte-macrophage lineage during virus infection of the bone marrow, the peripheral blood, the lymphoid tissues, and end organs such as the brain. The impact of genetic variation on LTR-directed transcription during the course of retrovirus disease is also reviewed

Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures.

BACKGROUND: HIV-1 entry is a receptor-mediated process directed by the interaction of the viral envelope with the host cell CD4 molecule and one of two co-receptors, CCR5 or CXCR4. The amino acid sequence of the third variable (V3) loop of the HIV-1 envelope is highly predictive of co-receptor utilization preference during entry, and machine learning predictive algorithms have been developed to characterize sequences as CCR5-utilizing (R5) or CXCR4-utilizing (X4). It was hypothesized that while the V3 loop is predominantly responsible for determining co-receptor binding, additional components of the HIV-1 genome may contribute to overall viral tropism and display sequence signatures associated with co-receptor utilization. RESULTS: The accessory protein Tat and the HlV-1 long terminal repeat (LTR) were analyzed with respect to genetic diversity and compared by Jensen-Shannon divergence which resulted in a correlation with both mean genetic diversity as well as the absolute difference in genetic diversity between R5- and X4-genome specific trends. As expected, the V3 domain of the gp120 protein was enriched with statistically divergent positions. Statistically divergent positions were also identified in Tat amino acid sequences within the transactivation and TAR-binding domains, and in nucleotide positions throughout the LTR. We further analyzed LTR sequences for putative transcription factor binding sites using the JASPAR transcription factor binding profile database and found several putative differences in transcription factor binding sites between R5 and X4 HIV-1 genomes, specifically identifying the C/EBP sites I and II, and Sp site III to differ with respect to sequence configuration for R5 and X4 LTRs. CONCLUSION: These observations support the hypothesis that co-receptor utilization coincides with specific genetic signatures in HIV-1 Tat and the LTR, likely due to differing transcriptional regulatory mechanisms and selective pressures applied within specific cellular targets during the course of productive HIV-1 infection

Variation of NO2 and NOx concentrations between and within 36 European study areas: Results from the ESCAPE study

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The effect of a patient centred care bundle intervention on pressure ulcer incidence (INTACT): a cluster randomised trial

Background: Hospital-acquired pressure ulcers are a serious patient safety concern, associated with poor patient outcomes and high healthcare costs. They are also viewed as an indicator of nursing care quality. Objective: To evaluate the effectiveness of a pressure ulcer prevention care bundle in preventing hospital-acquired pressure ulcers among at risk patients. Design: Pragmatic cluster randomised trial. Setting: Eight tertiary referral hospitals with >200 beds each in three Australian states. Participants: 1600 patients (200/hospital) were recruited. Patients were eligible if they were: ≥18 years old; at risk of pressure ulcer because of limited mobility; expected to stay in hospital ≥48 h and able to read English. Methods: Hospitals (clusters) were stratified in two groups by recent pressure ulcer rates and randomised within strata to either a pressure ulcer prevention care bundle or standard care. The care bundle was theoretically and empirically based on patient participation and clinical practice guidelines. It was multi-component, with three messages for patients’ participation in pressure ulcer prevention care: keep moving; look after your skin; and eat a healthy diet. Training aids for patients included a DVD, brochure and poster. Nurses in intervention hospitals were trained in partnering with patients in their pressure ulcer prevention care. The statistician, recruiters, and outcome assessors were blinded to group allocation and interventionists blinded to the study hypotheses, tested at both the cluster and patient level. The primary outcome, incidence of hospital-acquired pressure ulcers, which applied to both the cluster and individual participant level, was measured by daily skin inspection. Results: Four clusters were randomised to each group and 799 patients per group analysed. The intraclass correlation coefficient was 0.035. After adjusting for clustering and pre-specified covariates (age, pressure ulcer present at baseline, body mass index, reason for admission, residence and number of comorbidities on admission), the hazard ratio for new pressure ulcers developed (pressure ulcer prevention care bundle relative to standard care) was 0.58 (95% CI: 0.25, 1.33; p = 0.198). No adverse events or harms were reported. Conclusions: Although the pressure ulcer prevention care bundle was associated with a large reduction in the hazard of ulceration, there was a high degree of uncertainty around this estimate and the difference was not statistically significant. Possible explanations for this non-significant finding include that the pressure ulcer prevention care bundle was effective but the sample size too small to detect this