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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. Source

Hurst T.,University of Oxford | Pace M.,Peter Medawar Building for Pathogen Research | Katzourakis A.,University of Oxford | Phillips R.,Peter Medawar Building for Pathogen Research | 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. Source

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. Source

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. Source

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. Source

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