CD8+ T Cell Immunity in Human Immunodeficiency Virus-1 (HIV-1) Infection

A detailed understanding of the immune response to human immunodeficiency virus (HIV)-1 infection is needed to inform preventative and therapeutic strategies against HIV-1. HIV-1 specific CD8+ T cells contribute to control of HIV-1 throughout infection and will likely be an important component of any vaccine approach; however, it remains unclear what mechanisms of CD8+ T cell function mediate viral control. To that end, we analyzed samples from an acutely HIV-1 infected cohort and from persons living with HIV-1 (PLWH) durably suppressed on antiretroviral therapy (ART) to investigate the HIV-1 specific T cell response. In the latter group, we also explored the existence of pre-ART escape in the latent replication-competent HIV-1 reservoir, which contributes to HIV-1 rebound and may limit the capacity of T cells to detect and clear virally infected cells. Our studies show that HIV-1 infection induces a dynamic and robust HIV-1 specific CD8+ T cell response, with a large breadth of response that negatively correlated with viral load set point. The primary HIV-1 specific CD8+ T cell response was both highly activated and cytotoxic, and waned with the establishment of viral load set point. While total memory CD8+ T cells also expressed this phenotype, this phenotype was far more variable in human cytomegalovirus (HCMV)-specific CD8+ T cells. In the context of PLWH on ART, we report that while HIV-1 specific T cell targeting of the HIV-1 proteome was similar to patterns reported in untreated HIV-1 infection, the overall magnitude of the HIV-1 specific T cell response was ~10 fold lower than in untreated HIV-1 infection but remained detectable and highly stable. Importantly, we also report that the majority (68%) of virus variants in the latent HIV-1 reservoir did not escape T cell recognition, and that escape frequently occurred in less conserved regions of HIV-1. Collectively, our data suggest that circulating T cells in PLWH on ART could be harnessed for HIV-1 curative approaches, and that T cell immunotherapies shifting HIV-1 specific T cells to conserved regions of HIV-1 may mitigate past and future viral escape from T cells and overcome population level immunogenicity.Doctor of Philosoph

The symbiotic binary system RX Puppis: a possible recurrent nova with a Mira companion

We present an analysis of photometric and spectroscopic observations of the symbiotic binary system RX Pup with the aims of developing a reliable binary for the system and identifying mechanisms responsible for its spectacular activity. The binary is composed of a long-perod Mira variable surrounded by a thick dust shell and a hot white dwarf companion. The hot component produces practically all activity observed in the UV, optical and radio range, while variable obscuration of the Mira by circumstellar dust is responsible for long-term changes in the near-IR magnitudes. The observations show RX Pup underwent a nova-like eruption during the last three decades. The hot component contracted in radius at roughly constant luminosity from 1975 to 1986, and was the source of a strong stellar wind which prevented it from accreting material lost in the Mira wind. Around 1988/9 the hot component turned over in the HR diagram and by 1991 its luminosity had faded by a factor of about 30 with respect to the maximum plateau value and the hot wind had practically ceased. By 1995 the nova remnant started to accrete material from the Mira wind, as indicated by a general increase in intensity of the optical continuum and HI emission. The quiescent spectrum resembles the quiescent spectra of symbiotic recurrent novae, and its intensity indicates the hot component must accrete as much as about 1 per cent of the Mira wind, which is more or less the amount predicted by Bondi-Hoyle theory. The earliest observational records from the 1890s suggest that another nova-like eruption of RX Pup occurred around 1894.Comment: 23 pages, 12 figues, MNRAS - accepte

Population differentiation at a regional scale in spadefoot toads: contributions of distance and divergent selective environments

The causes of population differentiation can provide insight into the origins of early barriers to gene flow. Two key drivers of population differentiation are geographic distance and local adaptation to divergent selective environments. When reproductive isolation arises because some populations of a species are under selection to avoid hybridization while others are not, population differentiation and even speciation can result. Spadefoot toad populations Spea multiplicata that are sympatric with a congener have undergone reinforcement. This reinforcement has resulted not only in increased reproductive isolation from the congener, but also in the evolution of reproductive isolation from nearby and distant conspecific allopatric populations. We used multiple approaches to evaluate the contributions of geographic distance and divergent selective environments to population structure across this regional scale in S. multiplicata, based on genotypes from six nuclear microsatellite markers. We compared groups of populations varying in both geographic location and in the presence of a congener. Hierarchical F-statistics and results from cluster analyses and discriminant analyses of principal components all indicate that geographic distance is the stronger contributor to genetic differentiation among S. multiplicata populations at a regional scale. However, we found evidence that adaptation to divergent selective environments also contributes to population structure. Our findings highlight how variation in the balance of evolutionary forces acting across a species’ range can lead to variation in the relative contributions of geographic distance and local adaptation to population differentiation across different spatial scales

Harnessing CD8+ T Cells Under HIV Antiretroviral Therapy

Antiretroviral therapy (ART) has transformed HIV from a fatal disease to a chronic condition. In recent years there has been considerable interest in strategies to enable HIV-infected individuals to cease ART without viral rebound, either by purging all cells infected harboring replication-competent virus (HIV eradication), or by boosting immune responses to allow durable suppression of virus without rebound (HIV remission). Both of these approaches may need to harness HIV-specific CD8+ T cells to eliminate infected cells and/or prevent viral spread. In untreated infection, both HIV-specific and total CD8+ T cells are dysfunctional. Here, we review our current understanding of both global and HIV-specific CD8+ T cell immunity in HIV-infected individuals with durably suppressed viral load under ART, and its implications for HIV cure, eradication or remission. Overall, the literature indicates significant normalization of global T cell parameters, including CD4/8 ratio, activation status, and telomere length. Global characteristics of CD8+ T cells from HIV+ART+ individuals align more closely with those of HIV-seronegative individuals than of viremic HIV-infected individuals. However, markers of senescence remain elevated, leading to the hypothesis that immune aging is accelerated in HIV-infected individuals on ART. This phenomenon could have implications for attempts to prime de novo, or boost existing HIV-specific CD8+ T cell responses. A major challenge for both HIV cure and remission strategies is to elicit HIV-specific CD8+ T cell responses superior to that elicited by natural infection in terms of response kinetics, magnitude, breadth, viral suppressive capacity, and tissue localization. Addressing these issues will be critical to the success of HIV cure and remission attempts

Towards a grapho-phonologically parsed corpus of medieval Scots:Database design and technical solutions

This paper presents a newly constructed corpus of sound-to-spelling mappings in medieval Scots, which stems from the work of the From Inglis to Scots (FITS) project. We have developed a systematic approach to the relationships between individual spellings and proposed sound values, and recorded these mutual links in a relational database. In this paper, we introduce the theoretical underpinnings of sound-to-spelling and spelling-to-sound mappings, and show how a Scots root morpheme undergoes grapho-phonological parsing, the analytical procedure that is employed to break down spelling sequences into sound units. We explain the data collection and annotation for the FITS Corpus (Alcorn et al., forthcoming), drawing attention to the extensive meta-data which accompany each analysed unit of spelling and sound. The database records grammatical and lexical information about the root, the positional arrangement of segments within the root, labels for the nuclei, vowels and consonants, the morphological context, and extra-linguistic detail of the text a given root was taken from (date, place and text type). With this wealth of information, the FITS corpus is capable of answering complex queries about the sound and spelling systems of medieval Scots. We also suggest how our methodology can be transferred to other non-standardised spelling systems

Influenza and pneumococcal vaccine uptake among nursing home residents in Nottingham, England: a postal questionnaire survey

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown influenza vaccine uptake in UK nursing home residents to be low. Very little information exists regarding the uptake of pneumococcal vaccine in this population. The formulation of policies relating to the vaccination of residents has been proposed as a simple step that may help improve vaccine uptake in care homes.</p> <p>Methods</p> <p>A postal questionnaire was sent to matrons of all care homes with nursing within the Greater Nottingham area in January 2006. Non respondents were followed up with up to 3 phone calls.</p> <p>Results</p> <p>30% (16/53) of respondents reported having a policy addressing influenza vaccination and 15% (8/53) had a policy addressing pneumococcal vaccination. Seasonal influenza vaccine coverage in care homes with a vaccination policy was 87% compared with 84% in care homes without a policy (p = 0.47). The uptake of pneumococcal vaccination was found to be low, particularly in care homes with no vaccination policy. Coverage was 60% and 32% in care homes with and without a vaccination policy respectively (p = 0.06). This result was found to be statistically significant on multivariate analysis (p = 0.03, R = 0.46)</p> <p>Conclusion</p> <p>The uptake of influenza vaccine among care home residents in the Nottingham region is relatively high, although pneumococcal vaccine uptake is low. This study shows that there is an association between pneumococcal vaccine uptake and the existence of a vaccination policy in care homes, and highlights that few care homes have vaccination policies in place.</p

The rise in narghile (shisha, hookah) waterpipe tobacco smoking: A qualitative study of perceptions of smokers and non smokers

<p>Abstract</p> <p>Background</p> <p>The prevalence of waterpipe tobacco smoking (WTS) in the Middle East region and worldwide is increasing. There is evidence to indicate both short term and long term health effects of WTS, resulting in the issuance of an advisory note by the World Health Organization.</p> <p>Methods</p> <p>This research aimed at gaining an in-depth understanding of the factors contributing to the rise in WTS in Lebanon. Qualitative focus groups (25) and in-depth interviews (9) were conducted with adults in Lebanon in 2007. Participants were recruited to represent diversity in smoking status, gender, age groups and urban/rural residence. The interviews and focus groups were thematically analyzed, and recurrent themes noted and summarized.</p> <p>Results</p> <p>The main themes identified were availability, affordability, innovation, influence of media, lack of a policy framework, and the sensory characteristics evoked from WTS. Men and women, smokers and non-smokers, and younger and older participants differed in their emphases on the above themes. These themes, though specific to waterpipe, are similar to themes manipulated by the cigarette industry, and eventually controlled through tobacco control policies.</p> <p>Conclusions</p> <p>Understanding reasons behind the rise in waterpipe tobacco use is important if appropriate prevention, cessation, and policy interventions are to be formulated. Strict adherence to the FCTC is warranted, with careful and vigilant attention that all tobacco products are covered by laws in both high as well as middle to lower income countries.</p

Can computer-aided diagnosis assist in the identification of prostate cancer on prostate MRI? a multi-center, multi-reader investigation.

For prostate cancer detection on prostate multiparametric MRI (mpMRI), the Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) and computer-aided diagnosis (CAD) systems aim to widely improve standardization across radiologists and centers. Our goal was to evaluate CAD assistance in prostate cancer detection compared with conventional mpMRI interpretation in a diverse dataset acquired from five institutions tested by nine readers of varying experience levels, in total representing 14 globally spread institutions. Index lesion sensitivities of mpMRI-alone were 79% (whole prostate (WP)), 84% (peripheral zone (PZ)), 71% (transition zone (TZ)), similar to CAD at 76% (WP, p=0.39), 77% (PZ, p=0.07), 79% (TZ, p=0.15). Greatest CAD benefit was in TZ for moderately-experienced readers at PI-RADSv2 <3 (84% vs mpMRI-alone 67%, p=0.055). Detection agreement was unchanged but CAD-assisted read times improved (4.6 vs 3.4 minutes, p<0.001). At PI-RADSv2 ≥ 3, CAD improved patient-level specificity (72%) compared to mpMRI-alone (45%, p<0.001). PI-RADSv2 and CAD-assisted mpMRI interpretations have similar sensitivities across multiple sites and readers while CAD has potential to improve specificity and moderately-experienced radiologists' detection of more difficult tumors in the center of the gland. The multi-institutional evidence provided is essential to future prostate MRI and CAD development

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.This work was supported by: UK Medical Research Council Project Grants [MR/M00046X/1], [MR/R026440/1] and Project grant from National Institute of Health Research Biomedical Research Centre at Addenbrooke's Hospital (to E.R.), Fondazione Bambino Gesù (Vite Coraggiose) and Italian Ministry of Health (CCR-2017-23669081) (to M.T.), National Institute for Health Research (NIHR) for the Cambridge Biomedical Research Centre and NIHR BioResource (Grant Number RG65966) (to F.L.R.), and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 216370/Z/19/Z) (to J.E.). CIMR was supported by a Wellcome Trust Strategic Award [100140] and Equipment Grant [093026]. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support