CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome.

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression

Identifying key drivers of the impact of an HIV cure intervention in sub-Saharan Africa

BACKGROUND:  The properties required of an intervention that results in eradication or control of HIV in absence of antiretroviral therapy (ART-free viral suppression) to make it cost-effective in low income settings are unknown. METHODS:  We used a model of HIV and ART to investigate the effect of introducing an ART-free viral suppression intervention in 2022 in an example country of Zimbabwe. We assumed that the intervention (cost: $500) would be accessible for 90$300 million (8.7% saving). An intervention of this efficacy costing anything up to $1400 is likely to be cost-effective in this setting. CONCLUSION:  Interventions aimed at curing HIV have the potential to improve overall disease burden and to reduce costs. Given the effectiveness and cost of ART, such interventions would have to be inexpensive and highly effective

Improving soil and water management for agriculture: insights and innovation from Malta

Maltese soil resources are a precious and finite natural resource of great agricultural, environmental, and cultural value. They have been subject to human influence over a considerable time and, owing to prolonged intensive land use, have suffered from degradation by erosion, loss of organic matter, structural deterioration, and contamination from excess nitrates, agrochemicals, and salinity. Similarly, water resources (both quantity and quality) in Malta are also under severe stress owing to socio-economic development, over-abstraction for agricultural irrigation and from diffuse pollution. This paper briefly explores the key soil and water challenges facing farmers and the agricultural sector in Malta. Selected technology based and management innovations to improve resource use efficiency, sustain productivity, and support the agricultural sector are identified and discussed. The evidence forms part of FOWARIM ‘Fostering water-agriculture research and innovation in Malta’, an EC H2020-funded twinning project that is building research capacity, supporting knowledge exchange to practitioners, and providing evidence to inform policies for government and the agricultural sector in Malta

MRI-targeted or standard biopsy for prostate-cancer diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .)

Lessons to be learned from test evaluations during the Covid-19 pandemic:RSS Working Group’s Report on Diagnostic Tests

The coronavirus disease (Covid-19) pandemic raised challenges for everyday life. Development of new diagnostic tests was necessary, but under such enormous pressure risking inadequate evaluation. Against a background of concern about standards applied to the evaluation of in vitro diagnostic tests (IVDs), clear statistical thinking was needed on the principles of diagnostic testing in general, and their application in a pandemic. Therefore, in July 2020, the Royal Statistical Society convened a Working Group of six biostatisticians to review the statistical evidence needed to ensure the performance of new tests, especially IVDs for infectious diseases—for regulators, decision-makers, and the public. The Working Group’s review was undertaken when the Covid-19 pandemic shone an unforgiving light on current processes for evaluating and regulating IVDs for infectious diseases. The report’s findings apply more broadly than to the pandemic and IVDs, to diagnostic test evaluations in general. A section of the report focussed on lessons learned during the pandemic and aimed to contribute to the UK Covid-19 Inquiry’s examination of the response to, and impact of, the Covid-19 pandemic to learn lessons for the future. The review made 22 recommendations on what matters for study design, transparency, and regulation

Lessons to be learned from test evaluations during the Covid-19 pandemic:RSS Working Group’s Report on Diagnostic Tests

The coronavirus disease (Covid-19) pandemic raised challenges for everyday life. Development of new diagnostic tests was necessary, but under such enormous pressure risking inadequate evaluation. Against a background of concern about standards applied to the evaluation of in vitro diagnostic tests (IVDs), clear statistical thinking was needed on the principles of diagnostic testing in general, and their application in a pandemic. Therefore, in July 2020, the Royal Statistical Society convened a Working Group of six biostatisticians to review the statistical evidence needed to ensure the performance of new tests, especially IVDs for infectious diseases—for regulators, decision-makers, and the public. The Working Group’s review was undertaken when the Covid-19 pandemic shone an unforgiving light on current processes for evaluating and regulating IVDs for infectious diseases. The report’s findings apply more broadly than to the pandemic and IVDs, to diagnostic test evaluations in general. A section of the report focussed on lessons learned during the pandemic and aimed to contribute to the UK Covid-19 Inquiry’s examination of the response to, and impact of, the Covid-19 pandemic to learn lessons for the future. The review made 22 recommendations on what matters for study design, transparency, and regulation

Association Study of Common Genetic Variants and HIV- 1 Acquisition in 6,300 Infected Cases and 7,200 Controls

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception ofCCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size

In vivo emergence of HIV-1 highly sensitive to neutralizing antibodies.

BACKGROUND: The rapid and continual viral escape from neutralizing antibodies is well documented in HIV-1 infection. Here we report in vivo emergence of viruses with heightened sensitivity to neutralizing antibodies, sometimes paralleling the development of neutralization escape. METHODOLOGY/PRINCIPAL FINDINGS: Sequential viral envs were amplified from seven HIV-1 infected men monitored from seroconversion up to 5 years after infection. Env-recombinant infectious molecular clones were generated and tested for coreceptor use, macrophage tropism and neutralization sensitivity to homologous and heterologous serum, soluble CD4 and monoclonal antibodies IgG1b12, 2G12 and 17b. We found that HIV-1 evolves sensitivity to contemporaneous neutralizing antibodies during infection. Neutralization sensitive viruses grow out even when potent autologous neutralizing antibodies are present in patient serum. Increased sensitivity to neutralization was associated with susceptibility of the CD4 binding site or epitopes induced after CD4 binding, and mediated by complex envelope determinants including V3 and V4 residues. The development of neutralization sensitive viruses occurred without clinical progression, coreceptor switch or change in tropism for primary macrophages. CONCLUSIONS: We propose that an interplay of selective forces for greater virus replication efficiency without the need to resist neutralizing antibodies in a compartment protected from immune surveillance may explain the temporal course described here for the in vivo emergence of HIV-1 isolates with high sensitivity to neutralizing antibodies

Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]