Viral dynamics during structured treatment interruptions of chronic human immunodeficiency virus type 1 infection

Although antiviral agents which block human immunodeficiency virus (HIV) replication can result in long-term suppression of viral loads to undetectable levels in plasma, long-term therapy fails to eradicate virus, which generally rebounds after a single treatment interruption. Multiple structured treatment interruptions (STIs) have been suggested as a possible strategy that may boost HIV-specific immune responses and control viral replication. We analyze viral dynamics during four consecutive STI cycles in 12 chronically infected patients with a history (>2 years) of viral suppression under highly active antiretroviral therapy. We fitted a simple model of viral rebound to the viral load data from each patient by using a novel statistical approach that allows us to overcome problems of estimating viral dynamics parameters when there are many viral load measurements below the limit of detection. There is an approximate halving of the average viral growth rate between the first and fourth STI cycles, yet the average time between treatment interruption and detection of viral loads in the plasma is approximately the same in the first and fourth interruptions. We hypothesize that reseeding of viral reservoirs during treatment interruptions can account for this discrepancy, although factors such as stochastic effects and the strength of HIV-specific immune responses may also affect the time to viral rebound. We also demonstrate spontaneous drops in viral load in later STIs, which reflect fluctuations in the rates of viral production and/or clearance that may be caused by a complex interaction between virus and target cells and/or immune responses

Phenotypic hypersusceptibility to multiple protease inhibitors and low replicative capacity in patients who are chronically infected with human immunodeficiency virus type 1

Increased susceptibility to the protease inhibitors saquinavir and amprenavir has been observed in human immunodeficiency virus type 1 (HIV-1) with specific mutations in protease (V82T and N88S). Increased susceptibility to ritonavir has also been described in some viruses from antiretroviral agent-naïve patients with primary HIV-1 infection in association with combinations of amino acid changes at polymorphic sites in the protease. Many of the viruses displaying increased susceptibility to protease inhibitors also had low replication capacity. In this retrospective study, we analyze the drug susceptibility phenotype and the replication capacity of virus isolates obtained at the peaks of viremia during five consecutive structured treatment interruptions in 12 chronically HIV-1-infected patients. Ten out of 12 patients had at least one sample with protease inhibitor hypersusceptibility (change ≤0.4-fold) to one or more protease inhibitor. Hypersusceptibility to different protease inhibitors was observed at variable frequency, ranging from 38% to amprenavir to 11% to nelfinavir. Pairwise comparisons between susceptibilities for the protease inhibitors showed a consistent correlation among all pairs. There was also a significant relationship between susceptibility to protease inhibitors and replication capacity in all patients. Replication capacity remained stable over the course of repetitive cycles of structured treatment interruptions. We could find no association between in vitro replication capacity and in vivo plasma viral load doubling time and CD4(+) and CD8(+) T-cell counts at each treatment interruption. Several mutations were associated with hypersusceptibility to each protease inhibitor in a univariate analysis. This study extends the association between hypersusceptibility to protease inhibitors and low replication capacity to virus isolated from chronically infected patients and highlights the complexity of determining the genetic basis of this phenomenon. The potential clinical relevance of protease inhibitor hypersusceptibility and low replication capacity to virologic response to protease inhibitor-based therapies deserves to be investigated further

Landscape-scale assessments of stable carbon isotopes in soil under diverse vegetation classes in East Africa : application of near-infrared spectroscopy

Stable carbon isotopes are important tracers used to understand ecological food web processes and vegetation shifts over time. However, gaps exist in understanding soil and plant processes that influence delta C-13 values, particularly across smallholder farming systems in sub-Saharan Africa. This study aimed to develop predictive models for delta C-13 values in soil using near infrared spectroscopy (NIRS) to increase overall sample size. In addition, this study aimed to assess the delta C-13 values between five vegetation classes. The Land Degradation Surveillance Framework (LDSF) was used to collect a stratified random set of soil samples and to classify vegetation. A total of 154 topsoil and 186 subsoil samples were collected and analyzed using NIRS, organic carbon (OC) and stable carbon isotopes. Forested plots had the most negative average delta C-13 values, -26.1aEuro degrees; followed by woodland, -21.9aEuro degrees; cropland, -19.0aEuro degrees; shrubland, -16.5aEuro degrees; and grassland, -13.9aEuro degrees. Prediction models were developed for delta C-13 using partial least squares (PLS) regression and random forest (RF) models. Model performance was acceptable and similar with both models. The root mean square error of prediction (RMSEP) values for the three independent validation runs for delta C-13 using PLS ranged from 1.91 to 2.03 compared to 1.52 to 1.98 using RF. This model performance indicates that NIR can be used to predict delta C-13 in soil, which will allow for landscape-scale assessments to better understand carbon dynamics

Prevalence and Correlates of Herbal Medicine Use among Women Seeking Care for Infertility in Freetown, Sierra Leone

© 2018 Peter Bai James et al. In resource-poor countries where access to infertility care is limited, women may turn to traditional medicine to achieve motherhood. It is unknown whether Sierra Leonean women with such condition use herbal medicine. This study investigates the prevalence and factors associated with herbal medicine use among women seeking care for infertility. This was a questionnaire-based cross-sectional study conducted among women seeking care for infertility at various clinics within Freetown, Sierra Leone. Data analysis included Chi-square tests and logistic regression. Out of the 167 women that participated, 36.5% used herbal medicine for infertility treatment. Women with no formal (AOR 4.03, CL: 1.38-11.76, p=0.011), primary education (AOR: 6.23, CL: 2.02-19.23, p=0.001) and those that visited a traditional medicine practitioner (AOR: 20.05, CL: 2.10-192.28, p=0.009) as well as women suffering from other reproductive health problems (AOR: 2.57, CL: 1.13-5.83, p=0.024) were more likely to use herbal medicines. Friends and family (n=57, 96.7%) were the main influencers of herbal medicine use. Only (n=12) 19.7% of users disclosed their status to their healthcare provider. Over half (n=32, 52.5%) could not remember the name of the herb they used. Luffa acutangula (n=29, 100%) was the herbal medicinal plant users could recall. Herbal medicine use among women seeking care for infertility in Freetown is common. Healthcare providers should be aware of the potential dyadic use of herbal and allopathic medicines by their patients and be knowledgeable about commonly used herbal remedies as well as being proactive in communicating the potential risks and benefits associated with their use

Aging and Holography

Aging phenomena are examples of `non-equilibrium criticality' and can be exemplified by systems with Galilean and scaling symmetries but no time translation invariance. We realize aging holographically using a deformation of a non-relativistic version of gauge/gravity duality. Correlation functions of scalar operators are computed using holographic real-time techniques, and agree with field theory expectations. At least in this setup, general aging phenomena are reproduced holographically by complexifying the bulk space-time geometry, even in Lorentzian signature.Comment: 1 pdf figur

An Area‐Specific, International Community‐Led Approach to Understanding and Addressing Equality, Diversity, and Inclusion Issues within Supramolecular Chemistry

Diversity, equality, and inclusion (DEI/EDI) are pressing issues in chemistry and the natural sciences. In this Essay we share how an area‐specific approach is “calling in” the community so that it can act to address EDI issues, and support those who are marginalised. Women In Supramolecular Chemistry (WISC) is an international network that aims to support equality, diversity, and inclusion within supramolecular chemistry. WISC has taken a field‐specific approach using qualitative research methods with scientists to identify the support that is needed and the problems the supramolecular community needs to address. Herein, we present survey data from the community which highlight the barriers that are faced by those who take career breaks for any reason, a common example is maternity leave, and the importance of mentoring to aid progression post‐PhD. In conclusion, we set out an interdisciplinary and creative approach to addressing EDI issues within supramolecular chemistry

A large population sample of African HIV genomes from the 1980s reveals a reduction in subtype D over time associated with propensity for CXCR4 tropism

We present 109 near full-length HIV genomes amplified from blood serum samples obtained during early 1986 from across Uganda, which to our knowledge is the earliest and largest population sample from the initial phase of the HIV epidemic in Africa. Consensus sequences were made from paired-end Illumina reads with a target-capture approach to amplify HIV material following poor success with standard approaches. In comparisons with a smaller 'intermediate' genome dataset from 1998 to 1999 and a 'modern' genome dataset from 2007 to 2016, the proportion of subtype D was significantly higher initially, dropping from 67% (73/109), to 57% (26/46) to 17% (82/465) respectively (p < 0.0001). Subtype D has previously been shown to have a faster rate of disease progression than other subtypes in East African population studies, and to have a higher propensity to use the CXCR4 co-receptor ("X4 tropism"); associated with a decrease in time to AIDS. Here we find significant differences in predicted tropism between A1 and D subtypes in all three sample periods considered, which is particularly striking the 1986 sample: 66% (53/80) of subtype D env sequences were predicted to be X4 tropic compared with none of the 24 subtype A1. We also analysed the frequency of subtype in the envelope region of inter-subtype recombinants, and found that subtype A1 is over-represented in env, suggesting recombination and selection have acted to remove subtype D env from circulation. The reduction of subtype D frequency over three decades therefore appears to be a result of selective pressure against X4 tropism and its higher virulence. Lastly, we find a subtype D specific codon deletion at position 24 of the V3 loop, which may explain the higher propensity for subtype D to utilise X4 tropism

Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate

Transmission of Non-B HIV Subtypes in the United Kingdom Is Increasingly Driven by Large Non-Heterosexual Transmission Clusters

BACKGROUND: The United Kingdom human immunodeficiency virus (HIV) epidemic was historically dominated by HIV subtype B transmission among men who have sex with men (MSM). Now 50% of diagnoses and prevalent infections are among heterosexual individuals and mainly involve non-B subtypes. Between 2002 and 2010, the prevalence of non-B diagnoses among MSM increased from 5.4% to 17%, and this study focused on the drivers of this change. METHODS: Growth between 2007 and 2009 in transmission clusters among 14 000 subtype A1, C, D, and G sequences from the United Kingdom HIV Drug Resistance Database was analysed by risk group. RESULTS: Of 1148 clusters containing at least 2 sequences in 2007, >75% were pairs and >90% were heterosexual. Most clusters (71.4%) did not grow during the study period. Growth was significantly lower for small clusters and higher for clusters of ≥7 sequences, with the highest growth observed for clusters comprising sequences from MSM and people who inject drugs (PWID). Risk group (P< .0001), cluster size (P< .0001), and subtype (P< .01) were predictive of growth in a generalized linear model. DISCUSSION: Despite the increase in non-B subtypes associated with heterosexual transmission, MSM and PWID are at risk for non-B infections. Crossover of subtype C from heterosexuals to MSM has led to the expansion of this subtype within the United Kingdom

Virulence related sequences: insights provided by comparative genomics of Streptococcus uberis of differing virulence

Background: Streptococcus uberis, a Gram-positive, catalase-negative member of the family Streptococcaceae is an important environmental pathogen responsible for a significant proportion of subclinical and clinical bovine intramammary infections. Currently, the genome of only a single reference strain (0140J) has been described. Here we present a comparative analysis of complete draft genome sequences of an additional twelve S. uberis strains. Results: Pan and core genome analysis revealed the core genome common to all strains to be 1,550 genes in 1,509 orthologous clusters, complemented by 115-246 accessory genes present in one or more S. uberis strains but absent in the reference strain 0140J. Most of the previously predicted virulent genes were present in the core genome of all 13 strains but gene gain/loss was observed between the isolates in CDS associated with clustered regularly interspaced short palindromic repeats (CRISPRs), prophage and bacteriocin production. Experimental challenge experiments confirmed strain EF20 as non-virulent; only able to infect in a transient manner that did not result in clinical mastitis. Comparison of the genome sequence of EF20 with the validated virulent strain 0140J identified genes associated with virulence, however these did not relate clearly with clinical/non-clinical status of infection. Conclusion: The gain/loss of mobile genetic elements such as CRISPRs and prophage are a potential driving force for evolutionary change. This first “whole-genome” comparison of strains isolated from clinical vs non-clinical intramammary infections including the type virulent vs non-virulent strains did not identify simple gene gain/loss rules that readily explain, or be confidently associated with, differences in virulence. This suggests that a more complex dynamic determines infection potential and clinical outcome not simply gene content