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Hurst J.,John Radcliffe Hospital | Hurst J.,Institute for Emerging Infections | Hoffmann M.,John Radcliffe Hospital | Pace M.,John Radcliffe Hospital | And 28 more authors.
Nature Communications | Year: 2015

Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of 'post-treatment control' (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication. © 2015 Macmillan Publishers Limited. All rights reserved.


Frater J.,John Radcliffe Hospital | Frater J.,Peter Medawar Building for Pathogen Research | Frater J.,Institute for Emerging Infections | Frater J.,National Health Research Institute | And 22 more authors.
AIDS | Year: 2014

Objectives: Immune factors determining clinical progression following HIV-1 infection remain unclear. The SPARTAC trial randomized 366 participants in primary HIV infection (PHI) to different short-course therapies. The aim of this study was to investigate how early immune responses in PHI impacted clinical progression in SPARTAC. Design and methods: Participants with PHI recruited to the SPARTAC trial were sampled at enrolment, prior to commencing any therapy. HIV-1-specific CD4+ and CD8+ ELISpot responses were measured by gamma interferon ELISPOT. Immunological data were associated with baseline covariates and times to clinical progression using logistic regression, Kaplan-Meier plots, and Cox models. Results: Making a CD4+ T-cell ELISpot response (n=119) at enrolment was associated with higher CD4+ cell counts (P=0.02) and to some extent lower plasma HIV RNA (P=0.07). There was no correlation between the number of overlapping Gag CD8+ Tcell ELISpot responses (n=138) and plasma HIV-1 RNA viral load. Over a median follow-up of 2.9 years, baseline CD4+ cell ELISpot responses (n=119) were associated with slower clinical progression (P=0.01; log-rank). Over a median of 3.1 years, there was no evidence for a survival advantage imposed by CD8+ T-cell immunity (P=0.82). Conclusion: These data support a dominant protective role for CD4+ T-cell immunity in PHI compared with CD8+ T-cell responses, and are highly pertinent to HIV pathogenesis and vaccines, indicating that vaccine-induced CD4+ responses may confer sustained benefit. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Hurst T.,University of Oxford | Pace M.,John Radcliffe Hospital | Katzourakis A.,University of Oxford | Phillips R.,John Radcliffe Hospital | And 6 more authors.
Retrovirology | Year: 2016

Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences. Results: In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells. Conclusions: We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies. © 2016 Hurst et al.


Pace M.,Peter Medawar Building for Pathogen Research | Pace M.,Institute for Emerging Infections | Williams J.,Peter Medawar Building for Pathogen Research | Kurioka A.,Peter Medawar Building for Pathogen Research | And 11 more authors.
PLoS Pathogens | Year: 2016

In the search for a cure for HIV-1 infection, histone deacetylase inhibitors (HDACi) are being investigated as activators of latently infected CD4 T cells to promote their targeting by cytotoxic T-lymphocytes (CTL). However, HDACi may also inhibit CTL function, suggesting different immunotherapy approaches may need to be explored. Here, we study the impact of different HDACi on both Natural Killer (NK) and CTL targeting of HIV-1 infected cells. We found HDACi down-regulated HLA class I expression independently of HIV-1 Nef which, without significantly compromising CTL function, led to enhanced targeting by NK cells. HDACi-treated HIV-1-infected CD4 T cells were also more effectively cleared than untreated controls during NK co-culture. However, HDACi impaired NK function, reducing degranulation and killing capacity. Depending on the HDACi and dose, this impairment could counteract the benefit gained by treating infected target cells. These data suggest that following HDACi-induced HLA class I down-regulation NK cells kill HIV-1-infected cells, although HDACi-mediated NK cell inhibition may negate this effect. Our data emphasize the importance of studying the effects of potential interventions on both targets and effectors. © 2016 Pace et al.


Jones M.,Peter Medawar Building for Pathogen Research | Williams J.,Peter Medawar Building for Pathogen Research | Gartner K.,Peter Medawar Building for Pathogen Research | Phillips R.,Peter Medawar Building for Pathogen Research | And 7 more authors.
Journal of Virological Methods | Year: 2014

Droplet Digital PCR (ddPCR) represents a new and alternative platform to conventional quantitative-PCR (qPCR) for the quantitation of DNA templates. However, the proposed improvement in sensitivity and reproducibility offered by ddPCR is not yet fully proven, partly because the delineation between positive and negative responses is not always clear.Data are presented demonstrating the sensitivity of the ddPCR system to both reagent concentrations and choice of cut-off for defining positive and negative results. By implementing k-nearest clustering, cut-offs are produced that improve the accuracy of ddPCR where target DNA is present at low copy numbers, a key application of ddPCR. This approach is applied to human albumin and HIV-1 proviral DNA ddPCR quantitative protocols. This tool is coded in JavaScript and has been made available for free in a web browser at http://www.definetherain.org.uk. Optimisation of the analyses of raw ddPCR data using 'definetherain' indicates that low target number detection can be improved by its implementation. Further application to patient samples will help define the clinical utility of this approach. © 2014.


Roberts H.E.,University of Oxford | Goulder P.J.R.,University of Oxford | Goulder P.J.R.,University of KwaZulu - Natal | McLean A.R.,Institute for Emerging Infections | McLean A.R.,University of Oxford
Journal of the Royal Society Interface | Year: 2015

In HIV-infected patients, an individual's set point viral load (SPVL) strongly predicts disease progression. Some think that SPVL is evolving, indicating that the virulence of the virus may be changing, but the data are not consistent. In addition, the widespread use of antiretroviral therapy (ART) has the potential to drive virulence evolution. We develop a simple deterministic model designed to answer the following questions: what are the expected patterns of virulence change in the initial decades of an epidemic? Could administration of ART drive changes in virulence evolution and, what is the potential size and direction of this effect? We find that even without ART we would not expect monotonic changes in average virulence. Transient decreases in virulence following the peak of an epidemic are not necessarily indicative of eventual evolution to avirulence. In the short term, we would expect widespread ART to cause limited downward pressure on virulence. In the long term, the direction of the effect is determined by a threshold condition, which we define. We conclude that, given the surpassing benefits of ART to the individual and in reducing onward transmission, virulence evolution considerations need have little bearing on how we treat. © 2015 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.


Thornhill J.,Imperial College London | Fidler S.,Imperial College London | Frater J.,Collaborative HIV Eradication of Reservoirs UK BRC CHERUB | Frater J.,Peter Medawar Building for Pathogen Research | And 2 more authors.
Current Opinion in Infectious Diseases | Year: 2015

Purpose of review: To explore how ethical considerations, improved diagnostics and data from clinical trials might see the lowering of some of the barriers blocking a cure for HIV infection over the next 5 years. Recent findings: Despite the recent well publicized but eventually disappointing case reports, there remains only one successful HIV cure, the 'Berlin patient'. We will review the data suggesting that more potent agents might achieve in-vivo viral activation and explore the tantalizing phenomenon of 'posttreatment control' following treatment in primary HIV infection. We will also explore how new assays and novel interventions might move the field forward. Summary: There is a need for new agents that can be safely tested to impact the viral reservoir, a more meaningful understanding of how to assay patient samples, and research into mechanisms behind how the reservoir is established and impacted by therapy. With HIV+ve individuals responding so well to antiretroviral therapy, new trials must be tested hand-in-hand with guidance from patient representatives, especially with respect to determining the acceptable risk. The road to a cure is going to be difficult, but it is vital that inevitable disappointments do not detract from the final goal, which remains worth striving for. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


De Maio N.,Institute for Emerging Infections | De Maio N.,University of Oxford | Wu C.-H.,University of Oxford | O'Reilly K.M.,Imperial College London | And 2 more authors.
PLoS Genetics | Year: 2015

Phylogeographic methods aim to infer migration trends and the history of sampled lineages from genetic data. Applications of phylogeography are broad, and in the context of pathogens include the reconstruction of transmission histories and the origin and emergence of outbreaks. Phylogeographic inference based on bottom-up population genetics models is computationally expensive, and as a result faster alternatives based on the evolution of discrete traits have become popular. In this paper, we show that inference of migration rates and root locations based on discrete trait models is extremely unreliable and sensitive to biased sampling. To address this problem, we introduce BASTA (BAyesian STructured coalescent Approximation), a new approach implemented in BEAST2 that combines the accuracy of methods based on the structured coalescent with the computational efficiency required to handle more than just few populations. We illustrate the potentially severe implications of poor model choice for phylogeographic analyses by investigating the zoonotic transmission of Ebola virus. Whereas the structured coalescent analysis correctly infers that successive human Ebola outbreaks have been seeded by a large unsampled non-human reservoir population, the discrete trait analysis implausibly concludes that undetected human-to-human transmission has allowed the virus to persist over the past four decades. As genomics takes on an increasingly prominent role informing the control and prevention of infectious diseases, it will be vital that phylogeographic inference provides robust insights into transmission history. © 2015 De Maio et al.


Pace M.,University of Oxford | Pace M.,Institute for Emerging Infections | Frater J.,University of Oxford | Frater J.,Institute for Emerging Infections | Frater J.,National Health Research Institute
Expert Review of Anti-Infective Therapy | Year: 2014

HIV is a devastating disease affecting millions of people worldwide despite the advent of successful antiretroviral therapy (ART). However, ART does not result in a cure and has to be taken for life. Accordingly, researchers are turning towards cure efforts, particularly in the light of two patients whose HIV has been seemingly eradicated. Numerous approaches and strategies have been considered for curing HIV, but no scalable and safe solution has yet been reached. With newly discovered difficulties in measuring the HIV reservoir, the main barrier to a cure, the only true test of cure is to stop ART and see whether the virus becomes detectable. However, it is possible that this treatment interruption may be associated with certain risks for patients. Here, we compare the current major approaches and recent advances for curing HIV, as well as discuss ways of evaluating HIV cure and the safety concerns involved. © 2014 Informa UK, Ltd.


Palmer D.,University of Oxford | Palmer D.,Institute for Emerging Infections | Frater J.,Institute for Emerging Infections | Frater J.,University of Oxford | And 6 more authors.
Proceedings of the Royal Society B: Biological Sciences | Year: 2013

The rates of escape and reversion in response to selection pressure arising from the host immune system, notably the cytotoxic T-lymphocyte (CTL) response, are key factors determining the evolution of HIV. Existing methods for estimating these parameters from cross-sectional population data using ordinary differential equations (ODEs) ignore information about the genealogy of sampled HIV sequences, which has the potential to cause systematic bias and overestimate certainty. Here, we describe an integrated approach, validated through extensive simulations, which combines genealogical inference and epidemiological modelling, to estimate rates of CTL escape and reversion in HIV epitopes. We show that there is substantial uncertainty about rates of viral escape and reversion from cross-sectional data, which arises from the inherent stochasticity in the evolutionary process. By application to empirical data, we find that point estimates of rates from a previously published ODE model and the integrated approach presented here are often similar, but can also differ several-fold depending on the structure of the genealogy. The model-based approach we apply provides a framework for the statistical analysis and hypothesis testing of escape and reversion in population data and highlights the need for longitudinal and denser cross-sectional sampling to enable accurate estimate of these key parameters. © 2013 The Authors.

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