Biology subjects

Gupta, S.

Publications and source records attributed to Gupta, S..

28 records · Page 2Linked to original sources

bioRxiv2017

90-90-90, epidemic control, and ending AIDS: review of global situation and recommendations

HIV remains a devastating pandemic HIV remains a devastating... Ending AIDS The prevention vs. treatment... Economics of ending AIDS Major innovations accelerating... HIV self-tests Universal treatment regimen Comprehensive community-based... Standardized M and E... Unification of global leadership... Last mile strategies,... Conclusion References Although human immunodeficiency virus (HIV) first came to our attention thirty-seven years ago, the acquired immunodeficiency syndrome (AIDS) which it causes is, without treatment, 100% fatal with devastating consequences for millions of people1. More than 35 million people have already died of ...

epidemiology↗

bioRxiv2017

Two diseases, same person: moving towards a combined HIV and TB continuum of care

SettingThe Human Immunodeficiency Virus (HIV) and Mycobacterium tuberculosis syndemic remains a global public health threat. Separate HIV and TB global targets have been set, however, success will depend on achieving combined disease control objectives and care continua.\n\nObjectiveReview available policy, budgets and data to re-conceptualize TB and HIV disease control objectives by combining HIV and TB care continua.\n\nMethodsFor 22 WHO TB and TB/HIV priority countries, we used 2014 and 2015 data from the HIV90-90-90watch website, UNAIDS Aidsinfo, and WHO 2016 Global TB Report. Global resources available in TB and HIV/TB activities for 2003-2017 was collected from publically available sources.\n\nResultsIn 22 high burden countries people living with HIV (PLHIV) on ART ranged from 9-70%; viral suppression was 38-63%. TB treatment success ranged from 34-94% with 13 (43% HIV/TB burden) countries above 80% TB treatment success. From 2003-2017, global international and domestic resources for HIV-associated TB and TB averaged $2.6 billion per year; the total for 2003-2017 was 39 billion dollars.\n\nConclusionReviewing combined HIV and TB targets demonstrate disease control progress and challenges. Using an integrated HIV and TB continuum supports HIV and TB disease control efforts focused on improving both individual and public health.\n\nFundingNone

epidemiology↗

bioRxiv2017

Review of UNAIDS national estimates of men who have sex with men, gay dating application users, and HIV 90-90-90 data

BackgroundAchieving the 90-90-90 is essential to keep people alive and to end AIDS. Men who have sex with men (MSM) often have the least access to HIV services.\n\nPurposeEstimates for key populations are often unavailable, dated or have very wide confidence intervals and more accurate estimates are required.\n\nMethodsWe compared registered users from a major gay dating application (2016) from 29 countries with the latest available (2013-2016) UNAIDS estimates by country. We searched the Internet, PubMed, national surveillance reports, UNAIDS country reports, Presidents Emergency Plan for AIDS Relief (PEPFAR) 2016 and 2017 operational plans, and conference abstracts for the latest nationally representative continua for MSM.\n\nResultsOf comparison countries, only 18 countries had UNAIDS or other MSM population estimates in the public domain. UNAIDS estimates were larger than the gay dating application users in 9 countries, perhaps reflecting incomplete market penetration for the application. The gay dating application users in 9 countries were above the UNAIDS estimates; 8 were over 30% higher and three more than double the reported estimate. Seven partial or complete nationally representative care continua for MSM were published between 2010 and 2016. Among estimated MSM living with HIV, viral suppression varied between 42% (United States) to 99% (Denmark). The quality of the continua methods varied (quality data not shown).\n\nConclusion\"What is not monitored is not done\" and social media has significant promise to improve estimates to ensure that MSM and other vulnerable people living with HIV and their communities are not left behind on the way to ending AIDS.

epidemiology↗

bioRxiv2017

Distinct antibody-mediated selection in a narrow-source HIV-1 outbreak among Chinese former plasma donors

The HIV-1 envelope protein mutates rapidly to evade recognition and killing, and is a major target of the humoral immune response and in vaccine development. Identification of common antibody epitopes for vaccine development have been complicated by large variations on both virus (different infecting founder strains) and host genetic levels. We studied HIV-1 envelope gp120 evolution in 12 Chinese former plasma donors infected with a purportedly single founder virus, with the aim of identifying common antibody epitopes under immune selection. We found five amino acid sites to be under significant positive selection in [≥]50% of the patients, and 22 sites housing mutations consistent with antibody-mediated selection. Despite strong selection pressure, some sites housed a limited repertoire of amino acids. Structural modelling revealed that most sites were located on the exposed distal edge of the Gp120 trimer, whilst wholly invariant sites clustered within the centre of the protein complex. Four sites, flanking the V3 hypervariable loop of the Gp120, represent novel antibody epitopes that may be suitable as vaccine candidates.

immunology↗

bioRxiv2017

Reverse immunodynamics: a new method to identifying targets of protective immunity.

Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. We propose a novel methodology that combines predictions from epidemiological models with phylogenetic and structural analyses to identify such targets. Epidemiological models predict that strong immune selection can cause antigenic variants to exist in non-overlapping combinations. A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations among antigenic variants. We applied this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and found strong signatures of immune selection among certain regions of low variability which could render them ideal vaccine candidates.

epidemiology↗

bioRxiv2017

Utilising a Cohort Study of Hepatitis B Virus (HBV) Vaccine-Mediated Immunity in South African Children to Model Infection Dynamics: Can We Meet Global Targets for Elimination by 2030?

BackgroundSustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Deployment of a robust prophylactic vaccine and enhanced interventions for prevention of mother to child transmission (PMTCT) are cornerstones of elimination strategy. However, in light of the estimated global burden of 290 million cases, enhanced efforts are required to underpin optimisation of public health strategy. Robust analysis of population epidemiology is particularly crucial for populations in Africa made vulnerable by HIV co-infection, poverty, stigma and poor access to prevention, diagnosis and treatment.\n\nMethodsWe here set out to evaluate the current and future role of HBV vaccination and PMTCT as tools for elimination. We first investigated the current impact of paediatric vaccination in a cohort of children with and without HIV infection in Kimberley, South Africa. Second, we used these data to inform a new model to simulate the ongoing impact of preventive interventions. By applying these two approaches in parallel, we are able to determine both the current impact of interventions, and the future projected outcome of ongoing preventive strategies over time.\n\nResultsExisting efforts have been successful in reducing paediatric prevalence of HBV infection in this setting to <1%, demonstrating the success of the existing vaccine campaign. Our model predicts that, if consistently deployed, combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, such that a major public health impact is possible even without achieving elimination. However, the prevalence of HBV e-antigen (HBeAg)-positive carriers will decline more slowly, representing a persistent population reservoir. We show that HIV co-infection significantly reduces titres of vaccine-mediated antibody, but has a relatively minor role in influencing the projected time to elimination. Our model can also be applied to other settings in order to predict time to elimination based on specific interventions.\n\nConclusionsThrough extensive deployment of preventive strategies for HBV, significant positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be substantially longer than that proposed by current goals.

microbiology↗

bioRxiv2017

Engagement rules that underpin DBL-DARC interactions for ingress of Plasmodium knowlesi and Plasmodium vivax into human erythrocytes

The molecular mechanisms by which P. knowlesi and P. vivax invade human red blood cells have long been studied. Malaria parasite erythrocytic stages comprise of repeated bursts of parasites via cyclical invasion of host RBCs using dedicated receptor-ligand interactions. A family of erythrocyte-binding proteins (EBPs) from P. knowlesi and P. vivax attach to human Duffy antigen receptor for chemokines (DARC) via their Duffy binding-like domains (Pv-DBL and Pk-DBL respectively) for invasion. Here, we provide a comprehensive overview that presents new insights on the atomic resolution interactions that underpin the binding of human DARC with Pk/Pv-DBLs. Based on extensive structural and biochemical data, we provide a novel, testable and overarching interaction model that rationalizes even contradictory pieces of evidence that have so far existed in the literature on Pk/Pv-DBL/DARC binding determinants. We address the conundrum of how parasite-encoded Pk/Pv-DBLs recognize human DARC via its two sulfated tyrosine residues. We collate evidence for two distinct DARC integration sites on Pk/Pv-DBLs that together likely engage the DARCs sulfated extracellular domain. These analyses are important for both malaria vaccine and inhibitor development efforts that are targeted at abrogating Pk/Pv-DBL/DARC coupling as one avenue to prevent invasion of P. vivax into human red blood cells.

microbiology↗

bioRxiv2017

Vaccination Can Drive An Increase In Frequencies Of Antibiotic Resistance Among Non-Vaccine Serotypes Of Streptococcus pneumoniae

The bacterial pathogen Streptococcus pneumoniae is a major public health concern, being responsible for more than 1.5 million deaths annually through pneumonia, meningitis and septicemia. In spite of vaccination efforts, pneumococcal carriage and disease remain high, since available vaccines target only a subset of serotypes and vaccination is often accompanied by a rise in non-vaccine serotypes. Epidemiological studies suggest that such a change in serotype frequencies is often coupled with an increase of antibiotic resistance among non-vaccine serotypes. Building on previous multi-locus models for bacterial pathogen population structure, we have developed a theoretical framework incorporating variation in serotype and antibiotic resistance to examine how their associations may be affected by vaccination. Using this framework, we find that vaccination can result in rapid increase in frequency of pre-existing resistant variants of non-vaccine serotypes due to the removal of competition from vaccine serotypes.

epidemiology↗

bioRxiv2016

Genome-Wide Fitness Analyses of the Foodborne Pathogen Campylobacter jejuni in In Vitro and In Vivo Models

Infection by Campylobacter is recognised as the most common cause of foodborne bacterial illness worldwide. Faecal contamination of meat, especially chicken, during processing represents a key route of transmission to humans. There is currently no licenced vaccine and no Campylobacter-resistant chickens. In addition, preventative measures aimed at reducing environmental contamination and exposure of chickens to Campylobacter jejuni (biosecurity) have been ineffective. There is much interest in the factors/mechanisms that drive C. jejuni colonisation and infection of animals, and survival in the environment. It is anticipated that understanding these mechanisms will guide the development of effective intervention strategies to reduce the burden of C. jejuni infection. Here we present a comprehensive analysis of C. jejuni fitness during growth and survival within and outside hosts. A comparative analysis of transposon (Tn) gene inactivation libraries in three C. jejuni strains by Tn-seq demonstrated that a large proportion, 331 genes, of the C. jejuni genome is dedicated to (in vitro) growth. An extensive Tn library in C. jejuni M1cam (~10,000 mutants) was screened for the colonisation of commercial broiler chickens, survival in houseflies and under nutrient-rich and-poor conditions at low temperature, and infection of human gut epithelial cells. We report C. jejuni factors essential throughout its life cycle and we have identified genes that fulfil important roles across multiple conditions, including maf3, fliW, fliD, pflB and capM, as well as novel genes uniquely implicated in survival outside hosts. Taking a comprehensive screening approach has confirmed previous studies, that the flagella are central to the ability of C. jejuni to interact with its hosts. Future efforts should focus on how to exploit this knowledge to effectively control infections caused by C. jejuni.\n\nAuthor SummaryCampylobacter jejuni is the leading bacterial cause of human diarrhoeal disease. C. jejuni encounters and has to overcome a wide range of \"stress\" conditions whilst passing through the gastrointestinal tract of humans and other animals, during processing of food products, on/in food and in the environment. We have taken a comprehensive approach to understand the basis of C. jejuni growth and within/outside host survival, with the aim to inform future development of intervention strategies. Using a genome-wide transposon gene inactivation approach we identified genes core to the growth of C. jejuni. We also determined genes that were required during the colonisation of chickens, survival in the housefly and under nutrient-rich and -poor conditions at low temperature, and during interaction with human gut epithelial tissue culture cells. This study provides a comprehensive dataset linking C. jejuni genes to growth and survival in models relevant to its life cycle. Genes important across multiple models were identified as well as genes only required under specific conditions. We identified that a large proportion of the C. jejuni genome is dedicated to growth and that the flagella fulfil a prominent role in the interaction with hosts. Our data will aid development of effective control strategies.

microbiology↗

bioRxiv2016

Signatures of non-neutral processes within the population structure of Streptococcus pneumoniae

Populations of Streptococcus pneumoniae (SP) are typically structured into groups of closely related organisms or lineages, but it is not clear whether they are maintained by selection or neutral processes. Here, we attempt to address this question by applying a machine learning technique to SP whole genomes. Our results indicate that lineages evolved through immune selection on the groEL chaperone protein. The groEL protein is part of the groESL operon and enables a large range of proteins to fold correctly within the physical environment of the nasopharynx, thereby explaining why lineage structure is so stable within SP despite high levels of genetic transfer. SP is also antigenically diverse, exhibiting a variety of distinct capsular serotypes. Associations exist between lineage and capsular serotype but these can be easily perturbed, such as by vaccination. Overall, our analyses indicate that the evolution of SP can be conceptualized as the rearrangement of modular functional units occurring on several different timescales under different pressures: some patterns have locked in early (such as the epistatic interactions between groESL and a constellation of other genes) and preserve the differentiation of lineages, while others (such as the associations between capsular serotype and lineage) remain in continuous flux.

epidemiology↗