Publications by authors named "Stephane Hué"

71 Publications

Interactions between timing and transmissibility explain diverse flavivirus dynamics in Fiji.

Nat Commun 2021 03 15;12(1):1671. Epub 2021 Mar 15.

Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Zika virus (ZIKV) has caused large, brief outbreaks in isolated populations, however ZIKV can also persist at low levels over multiple years. The reasons for these diverse transmission dynamics remain poorly understood. In Fiji, which has experienced multiple large single-season dengue epidemics, there was evidence of multi-year transmission of ZIKV between 2013 and 2017. To identify factors that could explain these differences in dynamics between closely related mosquito-borne flaviviruses, we jointly fit a transmission dynamic model to surveillance, serological and molecular data. We estimate that the observed dynamics of ZIKV were the result of two key factors: strong seasonal effects, which created an ecologically optimal time of year for outbreaks; and introduction of ZIKV after this optimal time, which allowed ZIKV transmission to persist over multiple seasons. The ability to jointly fit to multiple data sources could help identify a similar range of possible outbreak dynamics in other settings.
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http://dx.doi.org/10.1038/s41467-021-21788-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961049PMC
March 2021

Number of HIV-1 founder variants is determined by the recency of the source partner infection.

Science 2020 07;369(6499):103-108

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

During sexual transmission, the high genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to developing effective infection control strategies. Little is known about the importance of the source partner during this bottleneck. To test the hypothesis that the source partner affects the number of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results suggest that acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple-founder variant transmission compared with acquiring infection from someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple-founder strain infections.
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http://dx.doi.org/10.1126/science.aba5443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116289PMC
July 2020

External Validation of an MRI-Derived Radiomics Model to Predict Biochemical Recurrence after Surgery for High-Risk Prostate Cancer.

Cancers (Basel) 2020 Mar 28;12(4). Epub 2020 Mar 28.

Department of Radiation Oncology, CHRU Brest, 29200 Brest, France.

Adjuvant radiotherapy after prostatectomy was recently challenged by early salvage radiotherapy, which highlighted the need for biomarkers to improve risk stratification. Therefore, we developed an MRI ADC map-derived radiomics model to predict biochemical recurrence (BCR) and BCR-free survival (bRFS) after surgery. Our goal in this work was to externally validate this radiomics-based prediction model.

Experimental Design: A total of 195 patients with a high recurrence risk of prostate cancer (pT3-4 and/or R1 and/or Gleason's score > 7) were retrospectively included in two institutions. Patients with postoperative PSA (Prostate Specific Antigen) > 0.04 ng/mL or lymph node involvement were excluded. Radiomics features were extracted from T2 and ADC delineated tumors. A total of 107 patients from Institution 1 were used to retrain the previously published model. The retrained model was then applied to 88 patients from Institution 2 for external validation. BCR predictions were evaluated using AUC (Area Under the Curve), accuracy, and bRFS using Kaplan-Meier curves.

Results: With a median follow-up of 46.3 months, 52/195 patients experienced BCR. In the retraining cohort, the clinical prediction model (combining the number of risk factors and postoperative PSA) demonstrated moderate predictive power (accuracy of 63%). The radiomics model (ADC-based SZE predicted BCR with an accuracy of 78% and allowed for significant stratification of patients for bRFS ( < 0.0001). In Institution 2, this radiomics model remained predictive of BCR (accuracy of 0.76%) contrary to the clinical model (accuracy of 0.56%).

Conclusions: The recently developed MRI ADC map-based radiomics model was validated in terms of its predictive accuracy of BCR and bRFS after prostatectomy in an external cohort.
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http://dx.doi.org/10.3390/cancers12040814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226108PMC
March 2020

Nosocomial transmission of influenza: A retrospective cross-sectional study using next generation sequencing at a hospital in England (2012-2014).

Influenza Other Respir Viruses 2019 11 19;13(6):556-563. Epub 2019 Sep 19.

Institute of Epidemiology and Health Care, UCL, London, UK.

Background: The extent of transmission of influenza in hospital settings is poorly understood. Next generation sequencing may improve this by providing information on the genetic relatedness of viral strains.

Objectives: We aimed to apply next generation sequencing to describe transmission in hospital and compare with methods based on routinely-collected data.

Methods: All influenza samples taken through routine care from patients at University College London Hospitals NHS Foundation Trust (September 2012 to March 2014) were included. We conducted Illumina sequencing and identified genetic clusters. We compared nosocomial transmission estimates defined using classical methods (based on time from admission to sample) and genetic clustering. We identified pairs of cases with space-time links and assessed genetic relatedness.

Results: We sequenced influenza sampled from 214 patients. There were 180 unique genetic strains, 16 (8.8%) of which seeded a new transmission chain. Nosocomial transmission was indicated for 32 (15.0%) cases using the classical definition and 34 (15.8%) based on genetic clustering. Of the 50 patients in a genetic cluster, 11 (22.0%) had known space-time links with other cases in the same cluster. Genetic distances between pairs of cases with space-time links were lower than for pairs without spatial links (P < .001).

Conclusions: Genetic data confirmed that nosocomial transmission contributes significantly to the hospital burden of influenza and elucidated transmission chains. Prospective next generation sequencing could support outbreak investigations and monitor the impact of infection and control measures.
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http://dx.doi.org/10.1111/irv.12679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800305PMC
November 2019

Sustained Low-Level Transmission of Zika and Chikungunya Viruses after Emergence in the Fiji Islands.

Emerg Infect Dis 2019 08;25(8):1535-1538

Zika and chikungunya viruses were first detected in Fiji in 2015. Examining surveillance and phylogenetic and serologic data, we found evidence of low-level transmission of Zika and chikungunya viruses during 2013-2017, in contrast to the major outbreaks caused by closely related virus strains in other Pacific Island countries.
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http://dx.doi.org/10.3201/eid2508.180524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649350PMC
August 2019

Human Immunodeficiency Virus Type 1 Phylodynamics to Detect and Characterize Active Transmission Clusters in North Carolina.

J Infect Dis 2020 03;221(8):1321-1330

Division of Infectious Diseases, University of North Carolina at Chapel Hill.

Background: Human immunodeficiency virus type 1 (HIV-1) phylodynamics can be used to monitor epidemic trends and help target prevention through identification and characterization of transmission clusters.

Methods: We analyzed HIV-1 pol sequences sampled in North Carolina from 1997 to 2014. Putative clusters were identified using maximum-likelihood trees and dated using Bayesian Markov Chain Monte Carlo inference. Active clusters were defined as clusters including internal nodes from 2009 to 2014. Effective reproductive numbers (Re) were estimated using birth-death models for large clusters that expanded ≥2-fold from 2009 to 2014.

Results: Of 14 921 persons, 7508 (50%) sequences were identified in 2264 clusters. Only 288 (13%) clusters were active from 2009 to 2014; 37 were large (10-36 members). Compared to smaller clusters, large clusters were increasingly populated by men and younger persons; however, nearly 60% included ≥1 women. Clusters with ≥3 members demonstrated assortative mixing by sex, age, and sample region. Of 15 large clusters with ≥2-fold expansion, nearly all had Re approximately 1 by 2014.

Conclusions: Phylodynamics revealed transmission cluster expansion in this densely sampled region and allowed estimates of Re to monitor active clusters, showing the propensity for steady, onward propagation. Associations with clustering and cluster characteristics vary by cluster size. Harnessing sequence-derived epidemiologic parameters within routine surveillance could allow refined monitoring of local subepidemics.
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http://dx.doi.org/10.1093/infdis/jiz176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325798PMC
March 2020

Ross River Virus Antibody Prevalence, Fiji Islands, 2013-2015.

Emerg Infect Dis 2019 04;25(4):827-830

A unique outbreak of Ross River virus (RRV) infection was reported in Fiji in 1979. In 2013, RRV seroprevalence among residents was 46.5% (362/778). Of the residents who were seronegative in 2013 and retested in 2015, 10.9% (21/192) had seroconverted to RRV, suggesting ongoing endemic circulation of RRV in Fiji.
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http://dx.doi.org/10.3201/eid2504.180694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433005PMC
April 2019

High clustering of acute HCV infections and high rate of associated STIs among Parisian HIV-positive male patients.

Int J Antimicrob Agents 2019 May 8;53(5):678-681. Epub 2019 Feb 8.

Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié-Salpêtrière, Department of Infectious Diseases, Paris, France.

Background: Increasing incidence of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-positive men having sex with men (MSM) has been described in recent years. Phylogenetic analyses of acute HCV infections were undertaken to characterize the dynamics during the epidemic in Paris, and associated sexually transmitted infections (STIs) were evaluated.

Methods: Sanger sequencing of polymerase gene was performed. Maximum likelihood phylogenies were reconstructed using FastTree 2.1 under a GTR+CAT model. Transmission chains were defined as clades with a branch probability ≥0.80 and intraclade genetic distances <0.02 nucleotide substitutions per sites. STIs detected ≤1 month before HCV diagnosis were considered.

Results: Among the 85 studied patients, at least 81.2% were MSM. Respectively, 47.6%, 39.0%, 11.0% and 2.4% were infected with genotypes 1a, 4d, 3a and 2k. At least 91.8% were co-infected with HIV. HCV re-infection was evidenced for 24.7% of patients and STIs for 20.0% of patients. Twenty-two transmission chains were identified, including 52 acute hepatitis C (11 pairs and 11 clusters from three to seven patients).

Conclusions: These results revealed strong clustering of acute HCV infections. Thus, rapid treatment of both chronic and acute infections is needed among this population to decrease the prevalence of HCV, in combination with preventive behavioural interventions.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.02.002DOI Listing
May 2019

Caution is needed in interpreting HIV transmission chains by ultradeep sequencing.

AIDS 2019 03;33(4):691-699

Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

Objectives: Molecular epidemiology is applied to various aspects of HIV transmission analyses. With ultradeep sequencing (UDS), in-depth characterization of transmission episodes involving minority variants is permitted. We explored HIV-1 epidemiological linkage and evaluated characteristics of transmission dynamics and transmitted drug resistance (TDR) detection through the added value of UDS.

Design: HIV pol gene fragments were sequenced by UDS and Sanger sequencing on samples of 70 HIV-1-infected, treatment-naive recently diagnosed MSM.

Methods: Pairwise genetic distances and maximum likelihood phylogenies were computed. Transmission events were identified as clades with branch support at least 70% and intraclade genetic difference less than 4.5%. TDR mutations were recognized from the TDR consensus list. Transmission directionality, directness and inoculum size were inferred from tree topologies.

Results: Both datasets concurred in the identification of seven transmission pairs and one cluster of three patients. With UDS, direction of transmission was inferred in four out of eight chains. Evidence for multiple founder viruses was found in two out of eight chains. No transmission of minority-resistant variants was evidenced. TDR mutations prevalence in protease and reverse transcriptase fragments was 4.3% with Sanger sequencing and 18.6% with UDS.

Conclusion: Although Sanger sequencing and UDS identified the same transmission chains, UDS provided additional information on founder viruses, direction of transmission and levels of TDR. Nevertheless, topology of clusters was not always consistent across gene fragments, calling for a cautious interpretation of the data. Moreover, unobserved intermediary links cannot be excluded. Phylogenetic analysis use as a forensic technique for HIV transmission investigations is risky.
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http://dx.doi.org/10.1097/QAD.0000000000002105DOI Listing
March 2019

Characterization update of HIV-1 M subtypes diversity and proposal for subtypes A and D sub-subtypes reclassification.

Retrovirology 2018 12 22;15(1):80. Epub 2018 Dec 22.

IAME, UMR 1137, Université Paris Diderot, INSERM, Paris, France.

Background: The large and constantly evolving HIV-1 pandemic has led to an increasingly complex diversity. Because of some taxonomic difficulties among the most diverse HIV-1 subtypes, and taking advantage of the large amount of sequence data generated in the recent years, we investigated novel lineage patterns among the main HIV-1 subtypes.

Results: All HIV full-length genomes available in public databases were analysed (n = 2017). Maximum likelihood phylogenies and pairwise genetic distance were obtained. Clustering patterns and mean distributions of genetic distances were compared within and across the current groups, subtypes and sub-subtypes of HIV-1 to detect and analyse any divergent lineages within previously defined HIV lineages. The level of genetic similarity observed between most HIV clades was deeply consistent with the current classification. However, both subtypes A and D showed evidence of further intra-subtype diversification not fully described by the nomenclature system at the time and could be divided into several distinct sub-subtypes.

Conclusions: With this work, we propose an updated nomenclature of sub-types A and D better reflecting their current genetic diversity and evolutionary patterns. Allowing a more accurate nomenclature and classification system is a necessary step for easier subtyping of HIV strains and a better detection or follow-up of viral epidemiology shifts.
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http://dx.doi.org/10.1186/s12977-018-0461-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303845PMC
December 2018

Prevalence and Transmission Dynamics of HIV-1 Transmitted Drug Resistance in a Southeastern Cohort.

Open Forum Infect Dis 2018 Aug 20;5(8):ofy178. Epub 2018 Jul 20.

Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina.

Background: Transmitted drug resistance (TDR) compromises clinical management and outcomes. Transmitted drug resistance surveillance and identification of growing transmission clusters are needed in the Southeast, the epicenter of the US HIV epidemic. Our study investigated prevalence and transmission dynamics in North Carolina.

Methods: We analyzed surveillance drug resistance mutations (SDRMs) using partial sequences from patients presenting to 2 large HIV outpatient clinics from 1997 to 2014. Transmitted drug resistance prevalence was defined as ≥1 SDRMs among antiretroviral therapy (ART)-naïve patients. Binomial regression was used to characterize prevalence by calendar year, drug class, and demographic and clinical factors. We assessed the transmission networks of patients with TDR with maximum likelihood trees and Bayesian methods including background sequences (n = 15 246).

Results: Among 1658 patients with pretherapy resistance testing, ≥1 SDRMs was identified in 199 patients, with an aggregate TDR prevalence of 12% (95% confidence interval, 10% to 14%) increasing over time ( = .02). Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs; 8%) was common, followed by nucleoside reverse transcriptase inhibitors (4%) and protease inhibitors (2%). Factors associated with TDR were being a man reporting sex with men, white race, young age, higher CD4 cell count, and being a member of a transmission cluster. Transmitted drug resistance was identified in 106 clusters ranging from 2 to 26 members. Cluster resistance was primarily NNRTI and dominated by ART-naïve patients or those with unknown ART initiation.

Conclusions: Moderate TDR prevalence persists in North Carolina, predominantly driven by NNRTI resistance. Most TDR cases were identified in transmission clusters, signifying multiple local transmission networks and TDR circulation among ART-naïve persons. Transmitted drug resistance surveillance can detect transmission networks and identify patients for enhanced services to promote early treatment.
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http://dx.doi.org/10.1093/ofid/ofy178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101542PMC
August 2018

Using paired serology and surveillance data to quantify dengue transmission and control during a large outbreak in Fiji.

Elife 2018 08 14;7. Epub 2018 Aug 14.

Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Dengue is a major health burden, but it can be challenging to examine transmission and evaluate control measures because outbreaks depend on multiple factors, including human population structure, prior immunity and climate. We combined population-representative paired sera collected before and after the 2013/14 dengue-3 outbreak in Fiji with surveillance data to determine how such factors influence transmission and control in island settings. Our results suggested the 10-19 year-old age group had the highest risk of infection, but we did not find strong evidence that other demographic or environmental risk factors were linked to seroconversion. A mathematical model jointly fitted to surveillance and serological data suggested that herd immunity and seasonally varying transmission could not explain observed dynamics. However, the model showed evidence of an additional reduction in transmission coinciding with a vector clean-up campaign, which may have contributed to the decline in cases in the later stages of the outbreak.
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http://dx.doi.org/10.7554/eLife.34848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092126PMC
August 2018

Leveraging Phylogenetics to Understand HIV Transmission and Partner Notification Networks.

J Acquir Immune Defic Syndr 2018 08;78(4):367-375

Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Background: Partner notification is an important component of public health test and treat interventions. To enhance this essential function, we assessed the potential for molecular methods to supplement routine partner notification and corroborate HIV networks.

Methods: All persons diagnosed with HIV infection in Wake County, NC, during 2012-2013 and their disclosed sexual partners were included in a sexual network. A data set containing HIV-1 pol sequences collected in NC during 1997-2014 from 15,246 persons was matched to HIV-positive persons in the network and used to identify putative transmission clusters. Both networks were compared.

Results: The partner notification network comprised 280 index cases and 383 sexual partners and high-risk social contacts (n = 131 HIV-positive). Of the 411 HIV-positive persons in the partner notification network, 181 (44%) did not match to a HIV sequence, 61 (15%) had sequences but were not identified in a transmission cluster, and 169 (41%) were identified in a transmission cluster. More than half (59%) of transmission clusters bridged sexual network partnerships that were not recognized in the partner notification; most of these clusters were dominated by men who have sex with men.

Conclusions: Partner notification and HIV sequence analysis provide complementary representations of the existent partnerships underlying the HIV transmission network. The partner notification network components were bridged by transmission clusters, particularly among components dominated by men who have sex with men. Supplementing the partner notification network with phylogenetic data highlighted avenues for intervention.
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http://dx.doi.org/10.1097/QAI.0000000000001695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058319PMC
August 2018

Phenotypic properties of envelope glycoproteins of transmitted HIV-1 variants from patients belonging to transmission chains.

AIDS 2018 09;32(14):1917-1926

Université de Tours et CHRU de Tours, Inserm U1259, Tours.

Objective: Transmission of HIV-1 involves a bottleneck in which generally a single HIV-1 variant from a diverse viral population in the transmitting partner establishes infection in the new host. It is still unclear to what extent this event is driven by specific properties of the transmitted viruses or the result of a stochastic process. Our study aimed to better characterize this phenomenon and define properties shared by transmitted viruses.

Design: We compared antigenic and functional properties of envelope glycoproteins of viral variants found during primary infection in 27 patients belonging to eight transmission chains.

Methods: We generated pseudotyped viruses expressing Env variants of the viral quasispecies infecting each patient and compared their sensitivity to neutralization by eight human monoclonal broadly neutralizing antibodies (HuMoNAbs). We also compared their infectious properties by measuring their infectivity and sensitivity to various entry inhibitors.

Results: Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity, providing evidence that the transmission bottleneck is mainly nonstochastic. Transmitted viruses were CCR5-tropic, sensitive to MVC, and resistant to soluble forms of CD4, irrespective of the cluster to which they belonged. They were also sensitive to HuMoNAbs that target V3, the CD4-binding site, and the MPER region, suggesting that the loss of these epitopes may compromise their capacity to be transmitted.

Conclusion: Our data suggest that the transmission bottleneck is governed by selective forces. How these forces confer an advantage to the transmitted virus has yet to be determined.
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http://dx.doi.org/10.1097/QAD.0000000000001906DOI Listing
September 2018

Non-disclosed men who have sex with men in UK HIV transmission networks: phylogenetic analysis of surveillance data.

Lancet HIV 2018 06;5(6):e309-e316

Institute of Evolutionary Biology, Ashworth Laboratories, University of Edinburgh, Edinburgh, UK.

Background: Patients who do not disclose their sexuality, including men who do not disclose same-sex behaviour, are difficult to characterise through traditional epidemiological approaches such as interviews. Using a recently developed method to detect large networks of viral sequences from time-resolved trees, we localised non-disclosed men who have sex with men (MSM) in UK transmission networks, gaining crucial insight into the behaviour of this group.

Methods: For this phylogenetic analysis, we obtained HIV pol sequences from the UK HIV Drug Resistance Database (UKRDB), a central repository for resistance tests done as part of routine clinical care throughout the UK. Sequence data are linked to demographic and clinical data held by the UK Collaborative HIV Cohort study and the national HIV/AIDS reporting system database. Initially, we reconstructed maximum likelihood phylogenies from these sequences, then sequences were selected for time-resolved analysis in BEAST if they were clustered with at least one other sequence at a genetic distance of 4·5% or less with support of at least 90%. We used time-resolved phylogenies to create networks by linking together nodes if sequences shared a common ancestor within the previous 5 years. We identified potential non-disclosed MSM (pnMSM), defined as self-reported heterosexual men who clustered only with men. We measured the network position of pnMSM, including betweenness (a measure of connectedness and importance) and assortativity (the propensity for nodes sharing attributes to link).

Findings: 14 405 individuals were in the network, including 8452 MSM, 1743 heterosexual women and 1341 heterosexual men. 249 pnMSM were identified (18·6% of all clustered heterosexual men) in the network. pnMSM were more likely to be black African (p<0·0001), less likely to be infected with subtype B (p=0·006), and were slightly older (p=0·002) than the MSM they clustered with. Mean betweenness centrality was lower for pnMSM than for MSM (1·31, 95% CI 0·48-2·15 in pnMSM vs 2·24, 0·98-3·51 in MSM; p=0·002), indicating that pnMSM were in peripheral positions in MSM clusters. Assortativity by risk group was higher than expected (0·037 vs -0·037, p=0·01) signifying that pnMSM were linked to each other. We found that self-reported heterosexual men were more likely to link MSM and heterosexual women than heterosexual women were to link MSM and heterosexual men (Fisher's exact test p=0·0004; OR 2·24) but the number of such transmission chains was small (only 54 in total vs 32 in women).

Interpretation: pnMSM are a subgroup distinct from both MSM and from heterosexual men. They are more likely to choose sexual partners who are also pnMSM and might exhibit lower-risk sexual behaviour than MSM (eg, choosing low-risk partners or consistently using condoms). Heterosexual men are the group most likely to be diagnosed with late-stage disease (ie, low CD4 counts) and non-disclosed MSM might put female partners at higher risk than heterosexual men because non-disclosed MSM have male partners. Hence, pnMSM require specific consideration to ensure they are included in public health interventions.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3018(18)30062-6DOI Listing
June 2018

HLA-associated polymorphisms in the HIV-2 capsid highlight key differences between HIV-1 and HIV-2 immune adaptation.

AIDS 2018 03;32(6):709-714

NDM Research Building, Nuffield Department of Clinical Medicine, University of Oxford, Oxford.

Objective: HIV-1 frequently adapts in response to immune pressure from cytotoxic T-lymphocytes (CTL). Many HIV-2 infected individuals have robust capsid-specific CTL responses associated with viral control. Despite this CTL pressure, adaptive changes in this key immunogenic HIV-2 protein have not previously been described. We sought to compare selective pressure on HIV-1 and HIV-2 capsids and identify HLA-associated viral polymorphisms in HIV-2.

Design And Methods: Bioinformatic algorithms to identify sites under positive and negative selective pressure and a statistical model of evolution to identify HLA-associated polymorphisms in HIV-2 was applied to sequences from a community cohort in Guinea-Bissau. IFN-γ ELISpots were used to compare T-cell responses to wild-type and variant epitopes.

Results: We identified greater purifying selection and less sites under positive selective pressure in HIV-2 compared with HIV-1. Five HIV-2 codons with HLA-associated polymorphisms were detected all within or around known or predicted CTL epitopes. One site was within the HLA-B58 SuperType (ST)-restricted epitope (TSTVEEQIQW), the HIV-2 equivalent of the HIV-1 TW10 epitope. In contrast to HIV-1, where a T→N mutation at position 3 is associated with resulting loss of CTL control, an E→D mutation at position 5 was observed in HIV-2. Robust CTL responses to the variant HIV-2 epitope were seen, suggesting that HIV-2 adaptation may be at the level of T-cell receptor recognition.

Conclusion: Greater constraints on evolution may exist in HIV-2, resulting in more purifying selection and different immune adaptation pathways in HIV-1 and HIV-2 capsids. This may allow CTL responses to persist in HIV-2.
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http://dx.doi.org/10.1097/QAD.0000000000001753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895130PMC
March 2018

Single-virion sequencing of lamivudine-treated HBV populations reveal population evolution dynamics and demographic history.

BMC Genomics 2017 Oct 27;18(1):829. Epub 2017 Oct 27.

Genome Institute of Singapore, Singapore, 138672, Singapore.

Background: Viral populations are complex, dynamic, and fast evolving. The evolution of groups of closely related viruses in a competitive environment is termed quasispecies. To fully understand the role that quasispecies play in viral evolution, characterizing the trajectories of viral genotypes in an evolving population is the key. In particular, long-range haplotype information for thousands of individual viruses is critical; yet generating this information is non-trivial. Popular deep sequencing methods generate relatively short reads that do not preserve linkage information, while third generation sequencing methods have higher error rates that make detection of low frequency mutations a bioinformatics challenge. Here we applied BAsE-Seq, an Illumina-based single-virion sequencing technology, to eight samples from four chronic hepatitis B (CHB) patients - once before antiviral treatment and once after viral rebound due to resistance.

Results: With single-virion sequencing, we obtained 248-8796 single-virion sequences per sample, which allowed us to find evidence for both hard and soft selective sweeps. We were able to reconstruct population demographic history that was independently verified by clinically collected data. We further verified four of the samples independently through PacBio SMRT and Illumina Pooled deep sequencing.

Conclusions: Overall, we showed that single-virion sequencing yields insight into viral evolution and population dynamics in an efficient and high throughput manner. We believe that single-virion sequencing is widely applicable to the study of viral evolution in the context of drug resistance and host adaptation, allows differentiation between soft or hard selective sweeps, and may be useful in the reconstruction of intra-host viral population demographic history.
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http://dx.doi.org/10.1186/s12864-017-4217-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660452PMC
October 2017

Rising prevalence of non-B HIV-1 subtypes in North Carolina and evidence for local onward transmission.

Virus Evol 2017 Jan 24;3(1):vex013. Epub 2017 May 24.

Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA.

HIV-1 diversity is increasing in North American and European cohorts which may have public health implications. However, little is known about non-B subtype diversity in the southern United States, despite the region being the epicenter of the nation's epidemic. We characterized HIV-1 diversity and transmission clusters to identify the extent to which non-B strains are transmitted locally. We conducted cross-sectional analyses of HIV-1 partial sequences collected from 1997 to 2014 from adults accessing routine clinical care in North Carolina (NC). Subtypes were evaluated using COMET and phylogenetic analysis. Putative transmission clusters were identified using maximum-likelihood trees. Clusters involving non-B strains were confirmed and their dates of origin were estimated using Bayesian phylogenetics. Data were combined with demographic information collected at the time of sample collection and country of origin for a subset of patients. Among 24,972 sequences from 15,246 persons, the non-B subtype prevalence increased from 0% to 3.46% over the study period. Of 325 persons with non-B subtypes, diversity was high with over 15 pure subtypes and recombinants; subtype C (28.9%) and CRF02_AG (24.0%) were most common. While identification of transmission clusters was lower for persons with non-B versus B subtypes, several local transmission clusters (≥3 persons) involving non-B subtypes were identified and all were presumably due to heterosexual transmission. Prevalence of non-B subtype diversity remains low in NC but a statistically significant rise was identified over time which likely reflects multiple importation. However, the combined phylogenetic clustering analysis reveals evidence for local onward transmission. Detection of these non-B clusters suggests heterosexual transmission and may guide diagnostic and prevention interventions.
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http://dx.doi.org/10.1093/ve/vex013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442504PMC
January 2017

Low risk of a sexually-transmitted Zika virus outbreak.

Lancet Infect Dis 2016 10 19;16(10):1100-1102. Epub 2016 Sep 19.

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.

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http://dx.doi.org/10.1016/S1473-3099(16)30324-3DOI Listing
October 2016

Hepatitis C virus quasispecies and pseudotype analysis from acute infection to chronicity in HIV-1 co-infected individuals.

Virology 2016 May 21;492:213-24. Epub 2016 Mar 21.

Division of Infection & Immunity, Faculty of Medical Sciences, University College London, United Kingdom; Wellcome Trust Africa Centre for Health and Population Sciences, University of KwaZulu, Natal, South Africa.

HIV-1 infected patients who acquire HCV infection have higher rates of chronicity and liver disease progression than patients with HCV mono-infection. Understanding early events in this pathogenic process is important. We applied single genome sequencing of the E1 to NS3 regions and viral pseudotype neutralization assays to explore the consequences of viral quasispecies evolution from pre-seroconversion to chronicity in four co-infected individuals (mean follow up 566 days). We observed that one to three founder viruses were transmitted. Relatively low viral sequence diversity, possibly related to an impaired immune response, due to HIV infection was observed in three patients. However, the fourth patient, after an early purifying selection displayed increasing E2 sequence evolution, possibly related to being on suppressive antiretroviral therapy. Viral pseudotypes generated from HCV variants showed relative resistance to neutralization by autologous plasma but not to plasma collected from later time points, confirming ongoing virus escape from antibody neutralization.
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http://dx.doi.org/10.1016/j.virol.2016.02.003DOI Listing
May 2016

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

J Infect Dis 2016 May 23;213(9):1410-8. Epub 2015 Dec 23.

Institute for Evolutionary Biology.

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.
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http://dx.doi.org/10.1093/infdis/jiv758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813743PMC
May 2016

A phylotype-based analysis highlights the role of drug-naive HIV-positive individuals in the transmission of antiretroviral resistance in the UK.

AIDS 2015 Sep;29(15):1917-25

aInstitut de Biologie Computationnelle, LIRMM, UMR5506 CNRS bMIVEGEC, CNRS 5290, IRD 224, Université de Montpellier, Montpellier, France cMRC Clinical Trial Unit at UCL dPublic Health England eChelsea & Westminster Hospital fUniversity College London gLondon School of Hygiene and Tropical Medicine, London, UK.

Objective: Antiretroviral-naive HIV-positive individuals contribute to the transmission of drug-resistant viruses, compromising first-line therapy. Using phylogenetic inference, we quantified the proportion of transmitted drug-resistance originating from a treatment-naive source.

Methods: Using a novel phylotype-based approach, 24 550 HIV-1 subtype B partial pol gene sequences from the UK HIV Drug Resistance database were analysed. Ongoing transmission of drug resistance amongst HIV-positive individuals was identified as phylotypes of at least three sequences with at least one shared drug resistance mutation, a maximum intra-clade genetic distance of 4.0% and a basal branch support at least 90%. The time of persistence of the transmission chains was estimated using a fast least-squares molecular clock inference approach.

Results: Around 70% of transmitted drug-resistance had a treatment-naive source. The most commonly transmitted mutations were L90M in the protease gene and K103N, T215D and T215S in reverse transcriptase. Reversion to wild type occurred at a low frequency and drug-independent reservoirs of resistance have persisted for up to 13 years.

Conclusion: These results illustrate the impact of viral fitness on the establishment of resistance reservoirs and support the notion that earlier diagnoses and treatment of HIV infections are warranted for counteracting the spread of antiretroviral resistance. Phylotype-based phylogenetic inference is an attractive approach for the routine surveillance of transmitted drug resistance in HIV as well as in other pathogens for which genotypic resistance data are available.
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http://dx.doi.org/10.1097/QAD.0000000000000768DOI Listing
September 2015

HIV Transmission Patterns Among Immigrant Latinos Illuminated by the Integration of Phylogenetic and Migration Data.

AIDS Res Hum Retroviruses 2015 Oct 24;31(10):973-80. Epub 2015 Aug 24.

1 Division of Infectious Diseases, School of Medicine, University of North Carolina , Chapel Hill, North Carolina.

Latinos represent a growing proportion of HIV cases in North Carolina (NC). Understanding how immigrants are involved in local HIV transmission is important to guide interventions. We used phylogenetics to characterize Latino involvement in local HIV transmission chains. Transmission clusters were identified from maximum-likelihood phylogenies constructed with HIV pol sequences from 177 Latinos and 1,496 non-Latinos receiving care in NC. Highly supported clusters involving one or more Latinos were characterized. Migration data were obtained from interviews and chart review. Factors associated with cluster membership were identified using log-binomial regression. Most Latinos were male (76%), immigrants (83%), and had HIV-1B (99%). Immigrants were more likely to report heterosexual risk (67% vs. 23%) than U.S.-born Latinos (p < 0.01). We identified 32 clusters that included one or more Latinos; these involved 53 Latinos (30%) and 41 non-Latinos. Immigrant and U.S.-born Latinos were equally likely to be in clusters, but immigrants were more likely to be in clusters with another Latino (78% vs. 29%; p = 0.02). Cluster composition by ethnicity and risk behavior varied by cluster size; larger clusters contained fewer immigrants and more men who have sex with men (MSM). Factors associated with immigrant membership in local transmission clusters included age <30 years [RR 2.34 (95% CI 1.47-3.73)], Mexican origin [RR 2.55 (95% CI 1.29-6.88)], and residing in the United States longer before diagnosis [RR 1.53 (95% CI 1.09-2.15), per 10 years]. While some Latinos immigrate with HIV infection, many immigrants are involved in transmission networks after arrival, particularly MSM. HIV testing and prevention interventions must consider this heterogeneity and may be better targeted by integrating phylogenetic analyses.
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http://dx.doi.org/10.1089/AID.2015.0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576933PMC
October 2015

Positive Selection Analysis of Overlapping Reading Frames Is Invalid.

AIDS Res Hum Retroviruses 2015 Oct 22;31(10):947. Epub 2015 Jul 22.

2 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine , London, United Kingdom .

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http://dx.doi.org/10.1089/AID.2015.0150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118959PMC
October 2015

Intrapatient Evolutionary Dynamics of Human Immunodeficiency Virus Type 1 in Individuals Undergoing Alternative Treatment Strategies with Reverse Transcriptase Inhibitors.

AIDS Res Hum Retroviruses 2015 Jul 4;31(7):749-56. Epub 2015 Jun 4.

3 Virus Reference Department, Public Health England , London, United Kingdom .

Structured treatment interruption (STI) has been trialed as an alternative to lifelong antiretroviral therapy (ART). We retrospectively performed single genome sequencing of the HIV-1 pol region from three patients representing different scenarios. They were either failing on continuous therapy (CT-F), failing STI (STI-F), or suppressing on STI (STI-S). Over 460 genomes were generated from three to five different time points over a 2-year period. We found multiple-linked-resistant mutations in both treatment failures. However, the CT-F patient showed a stepwise accumulation of diverse, linked mutations whereas the STI-F patient had lineage turnover between treatment periods with recirculation of wild-type and resistant variants from reservoirs. The STI-F patient showed a 7-fold increase in the third codon position substitution rate relative to the first and second positions compared to a 2-fold increase for CT-F and increased purifying selection in the pol gene (62 vs. 22 sites, respectively). An understanding of intrapatient viral dynamics could guide the future direction of treatment interruption strategies.
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http://dx.doi.org/10.1089/AID.2015.0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505773PMC
July 2015

Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

J Acquir Immune Defic Syndr 2015 Jun;69(2):138-44

*Division of Infection and Immunity, University College London, London United Kingdom; †Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; ‡Children's Infectious Diseases Clinical Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; §Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; ||HJF-DAIDS, a Division of the Henry M Jackson Foundation for the Advancement of Military Medicine Inc, Contractor, NIAID, NIH, Department of Health and Human Services, Bethesda, MD; ¶Anova Health Institute, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; and #Africa Centre for Health and Population Studies, University of KwaZulu Natal.

The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited.
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http://dx.doi.org/10.1097/QAI.0000000000000568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679142PMC
June 2015

G2/M cell cycle arrest correlates with primate lentiviral Vpr interaction with the SLX4 complex.

J Virol 2015 Jan 15;89(1):230-40. Epub 2014 Oct 15.

Department of Infectious Diseases, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom

Unlabelled: The accessory gene vpr, common to all primate lentiviruses, induces potent G2/M arrest in cycling cells. A recent study showed that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) mediates this through activation of the SLX4/MUS81/EME1 exonuclease complex that forms part of the Fanconi anemia DNA repair pathway. To confirm these observations, we have examined the G2/M arrest phenotypes of a panel of simian immunodeficiency virus (SIV) Vpr proteins. We show that SIV Vpr proteins differ in their ability to promote cell cycle arrest in human cells. While this is dependent on the DCAF1/DDB1/CUL4 ubiquitin ligase complex, interaction with human DCAF1 does not predict G2/M arrest activity of SIV Vpr in human cells. In all cases, SIV Vpr-mediated cell cycle arrest in human cells correlated with interaction with human SLX4 (huSLX4) and could be abolished by small interfering RNA (siRNA) depletion of any member of the SLX4 complex. In contrast, all but one of the HIV/SIV Vpr proteins tested, including those that lacked activity in human cells, were competent for G2/M arrest in grivet cells. Correspondingly, here cell cycle arrest correlated with interaction with the grivet orthologues of the SLX4 complex, suggesting a level of host adaptation in these interactions. Phylogenetic analyses strongly suggest that G2/M arrest/SLX4 interactions are ancestral activities of primate lentiviral Vpr proteins and that the ability to dysregulate the Fanconi anemia DNA repair pathway is an essential function of Vpr in vivo.

Importance: The Vpr protein of HIV-1 and related viruses is essential for the virus in vivo. The ability of Vpr to block the cell cycle at mitotic entry is well known, but the importance of this function for viral replication is unclear. Recent data have shown that HIV-1 Vpr targets the Fanconi anemia DNA repair pathway by interacting with and activating an endonuclease complex, SLX4/MUS81/EME1, that processes interstrand DNA cross-links. Here we show that the ability of a panel of SIV Vpr proteins to mediate cell cycle arrest correlates with species-specific interactions with the SLX4 complex in human and primate cells. The results of these studies suggest that the SLX4 complex is a conserved target of primate lentiviral Vpr proteins and that the ability to dysregulate members of the Fanconi anemia DNA repair pathway is essential for HIV/SIV replication in vivo.
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http://dx.doi.org/10.1128/JVI.02307-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301105PMC
January 2015

Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length Gag-protease genes.

J Antimicrob Chemother 2014 Dec 4;69(12):3340-8. Epub 2014 Aug 4.

Division of Infection and Immunity, University College London, London, UK

Objectives: Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping.

Methods: Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated.

Results: >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6-8.35) to FC 13 (95% CI 8.11-17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals.

Discussion: This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure.
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http://dx.doi.org/10.1093/jac/dku296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228778PMC
December 2014

Phylogenetic analyses reveal HIV-1 infections between men misclassified as heterosexual transmissions.

AIDS 2014 Aug;28(13):1967-75

aDepartment of Infection, University College London bHIV and STI Department, Public Health England, London cSchool of Biological Sciences, University of Edinburgh, Edinburgh dInstitute of Biodiversity, University of Glasgow, Glasgow eMedical Research Council Clinical Trial Unit fHIV and Sexual Health Clinic, Chelsea and Westminster Hospital, London, UK.

Objective: HIV-1 subtype B infections are associated with MSM in the UK. Yet, around 13% of subtype B infections are found in those reporting heterosexual contact as transmission route. Using phylogenetics, we explored possible misclassification of sexual exposure among men diagnosed with HIV in the UK.

Design: Viral gene sequences linked to patient-derived information were used to identify phylogenetic transmission chains.

Methods: A total of 22,481 HIV-1 subtype B pol gene sequences sampled between 1996 and 2008 were analysed. Dated phylogenies were reconstructed and transmission clusters identified as clades of at least two sequences with a maximum genetic distance of 4.5%, a branch support of at least 95% and spanning 5 years. The characteristics of clusters containing at least one heterosexually acquired infection were analysed.

Results: Twenty-nine percent of the linked heterosexuals clustered exclusively with MSM. These were more likely to be men than women. Estimated misclassification of homosexually acquired infections ranged between 1 and 11% of the reported male heterosexuals diagnosed with HIV. Black African heterosexual men were more often phylogenetically linked to MSM than other ethnic group, with an estimated misclassification range between 1 and 21%.

Conclusion: Overall, a small proportion of self-reported heterosexual men diagnosed with HIV could have been infected homosexually. However, up to one in five black African heterosexual men chose not to disclose sex with men at HIV diagnosis and preferred to be identified as heterosexual. Phylogenetic analyses can enhance surveillance-based risk information and inform national programmes for monitoring and preventing HIV infections.
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http://dx.doi.org/10.1097/QAD.0000000000000383DOI Listing
August 2014

New insights into an X-traordinary viral protein.

Front Microbiol 2014 8;5:126. Epub 2014 Apr 8.

Department of Infectious Diseases, King's College London London, UK.

Vpx is a protein encoded by members of the HIV-2/SIVsmm and SIVrcm/SIVmnd-2 lineages of primate lentiviruses, and is packaged into viral particles. Vpx plays a critical role during the early steps of the viral life cycle and has been shown to counteract SAMHD1, a restriction factor in myeloid and resting T cells. However, it is becoming evident that Vpx is a multifunctional protein in that SAMHD1 antagonism is likely not its sole role. This review summarizes the current knowledge on this X-traordinary protein.
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http://dx.doi.org/10.3389/fmicb.2014.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986551PMC
June 2014