Analysis of infectious virus clones from two HIV-1 superinfection cases suggests that the primary strains have lower fitness

<p>Abstract</p> <p>Background</p> <p>Two HIV-1 positive patients, L and P, participating in the Amsterdam Cohort studies acquired an HIV-1 superinfection within half a year from their primary HIV-1 infection (Jurriaans <it>et al</it>., <it>JAIDS </it>2008, <b>47:</b>69-73). The aim of this study was to compare the replicative fitness of the primary and superinfecting HIV-1 strains of both patients. The use of isolate-specific primer sets indicated that the primary and secondary strains co-exist in plasma at all time points after the moment of superinfection.</p> <p>Results</p> <p>Biological HIV-1 clones were derived from peripheral blood CD4 + T cells at different time point, and identified as the primary or secondary virus through sequence analysis. Replication competition assays were performed with selected virus pairs in PHA/IL-2 activated peripheral blood mononuclear cells (PBMC's) and analyzed with the Heteroduplex Tracking Assay (HTA) and isolate-specific PCR amplification. In both cases, we found a replicative advantage of the secondary HIV-1 strain over the primary virus. Full-length HIV-1 genomes were sequenced to find possible explanations for the difference in replication capacity. Mutations that could negatively affect viral replication were identified in the primary infecting strains. In patient L, the primary strain has two insertions in the LTR promoter, combined with a mutation in the <it>tat </it>gene that has been associated with decreased replication capacity. The primary HIV-1 strain isolated from patient P has two mutations in the LTR that have been associated with a reduced replication rate. In a luciferase assay, only the LTR from the primary virus of patient P had lower transcriptional activity compared with the superinfecting virus.</p> <p>Conclusions</p> <p>These preliminary findings suggest the interesting scenario that superinfection occurs preferentially in patients infected with a relatively attenuated HIV-1 isolate.</p

Comparative Expression Profile of miRNA and mRNA in Primary Peripheral Blood Mononuclear Cells Infected with Human Immunodeficiency Virus (HIV-1)

Host cells respond to exogenous infectious agents such as viruses, including HIV-1. Studies have evaluated the changes associated with virus infection at the transcriptional and translational levels of the cellular genes involved in specific pathways. While this approach is useful, in our view it provides only a partial view of genome-wide changes. Recently, technological advances in the expression profiling at the microRNA (miRNA) and mRNA levels have made it possible to evaluate the changes in the components of multiple pathways. To understand the role of miRNA and its interplay with host cellular gene expression (mRNA) during HIV-1 infection, we performed a comparative global miRNA and mRNA microarray using human PBMCs infected with HIV-1. The PBMCs were derived from multiple donors and were infected with virus generated from the molecular clone pNL4-3. The results showed that HIV-1 infection led to altered regulation of 21 miRNAs and 444 mRNA more than 2-fold, with a statistical significance of p<0.05. Furthermore, the differentially regulated miRNA and mRNA were shown to be associated with host cellular pathways involved in cell cycle/proliferation, apoptosis, T-cell signaling, and immune activation. We also observed a number of inverse correlations of miRNA and mRNA expression in infected PBMCs, further confirming the interrelationship between miRNA and mRNA regulation during HIV-1 infection. These results for the first time provide evidence that the miRNA profile could be an early indicator of host cellular dysfunction induced by HIV-1

Host Genetics and HIV-1: The Final Phase?

This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host

Identifying perceived barriers to monitoring service quality among substance abuse treatment providers in South Africa

Background: A performance measurement system is planned for South African substance abuse treatment services. Provider-level barriers to implementing these systems have been identified in the United States, but little is known about the nature of these barriers in South Africa. This study explored the willingness of South African substance abuse treatment providers' to adopt a performance measurement system and perceived barriers to monitoring service quality that would need to be addressed during system development. Methods: Three focus group discussions were held with treatment providers from two of the nine provinces in South Africa. These providers represented the diverse spread of substance abuse treatment services available in the country. The final sample comprised 21 representatives from 12 treatment facilities: eight treatment centres in the Western Cape and four in KwaZulu-Natal. Content analysis was used to extract core themes from these discussions. Results: Participants identified barriers to the monitoring of service quality that included outdated modes of collecting data, personnel who were already burdened by paperwork, lack of time to collect data, and limited skills to analyse and interpret data. Participants recommended that developers engage with service providers in a participatory manner to ensure that service providers are invested in the proposed performance measurement system. Conclusion: Findings show that substance abuse treatment providers are willing to adopt a performance measurement system and highlight several barriers that need to be addressed during system development in order to enhance the likelihood that this system will be successfully implemented. © 2014 Myers et al.; licensee BioMed Central Ltd

Substance use history in behavioral-variant frontotemporal dementia versus primary progressive aphasia

BACKGROUND: As older adults are prone to cognitive disorders, the interaction of the fields of substance use and misuse and cognitive neuroscience is an emerging area of research. Substance use has been reported in some subtypes of frontotemporal dementia (FTD), such as behavioral variant frontotemporal dementia (bvFTD). However, characterization of substance use in other subtypes of FTD, such as primary progressive aphasia (PPAPH), is unknown. OBJECTIVE: The objective of this baseline analysis was to explore whether any measures of substance use history differed significantly among bvFTD (n = 842) and PPAPH (n = 526) in a large national dataset. DESIGN/METHODS: The National Alzheimer’s Coordinating Center’s (NACC) Uniform Data Set (UDS) study is a national dataset that collects data on patients with various cognitive disorders and includes some questions on substance use. We used each substance use variable as the outcome and the FTD subtype as the predictor. RESULTS: Total years smoked cigarettes, age when last smoked cigarettes, and average # of packs/day smoked when participants smoked, and any recent, remote, or combined recent/remote history of alcohol abuse or drug abuse did not significantly differ between the bvFTD and PPAPH subtypes (all p-values > 0.001). A significantly greater percentage of participants smoked in the last 30 days in the bvFTD subtype (10.4%, n = 834) compared to the PPAPH subtype (3.3%, n = 517) (p < 0.001). DISCUSSION: Clinical providers in both the dementia and substance use fields are encouraged to screen for and monitor substance use in all FTD subtypes