Imperial College London

ProfessorJonathanWeber

Faculty of MedicineFaculty of Medicine Centre

Dean of the Faculty of Medicine
 
 
 
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Contact

 

+44 (0)20 7594 3905j.weber

 
 
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Assistant

 

Mrs Siobhan Pigott +44 (0)20 7594 3901

 
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Location

 

2.15Faculty BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

291 results found

Zilber E, Martin GE, Willberg CB, Fox J, Nwokolo N, Fidler S, Frater J, CHERUB Investigatorset al., 2019, Soluble plasma programmed death 1 (PD-1) and Tim-3 in primary HIV infection., AIDS, Vol: 33, Pages: 1253-1256

: Soluble forms of the coinhibitory receptors programmed death 1 (PD-1) and Tim-3 exist, but their relationship with T-cell surface expression remains unclear. When measured by an enzyme-linked immunosorbent assay in plasma, soluble PD-1, and soluble Tim-3 were elevated during primary HIV infection, decreased on antiretroviral therapy to levels found in controls, and correlated with cell surface expression. We conclude that soluble PD-1 and soluble Tim-3 are easy to measure biomarkers of immune exhaustion which potentially eliminate the need for flow cytometry.

Journal article

Nadai Y, Held K, Joseph S, Ahmed MIM, Hoffmann VS, Peterhoff D, Missange M, Bauer A, Joachim A, Reimer U, Zerweck J, McCormack S, Cope A, Tatoud R, Shattock RJ, Robb ML, Sandstroem EG, Hoelscher M, Maboko L, Bakari M, Kroidl A, Wagner R, Weber J, Pollakis G, Geldmacher Cet al., 2019, Envelope-Specific Recognition Patterns of HIV Vaccine-Induced IgG Antibodies Are Linked to Immunogen Structure and Sequence, FRONTIERS IN IMMUNOLOGY, Vol: 10, ISSN: 1664-3224

Journal article

Geretti AM, White E, Orkin C, Tostevin A, Tilston P, Chadwick D, Leen C, Sabin C, Dunn DT, Asboe D, Asboe D, Pozniak A, Cane P, Chadwick D, Churchill D, Clark D, Collins S, Delpech V, Douthwaite S, Dunn D, Fearnhill E, Porter K, Tostevin A, Stirrup O, Fraser C, Gunson R, Hale A, Hue S, Lazarus L, Leigh-Brown A, Mbisa T, Mackie N, Orkin C, Nastouli E, Pillay D, Phillips A, Sabin C, Smit E, Templeton K, Tilston P, Volz E, Williams I, Zhang H, Dawkins J, O'Shea S, Mullen J, Smit E, Mbisa T, Cox A, Tandy R, Fawcett T, Hopkins M, Tilston P, Booth C, Garcia-Diaz A, Renwick L, Schmid ML, Payne B, Chadwick D, Hubb J, Dustan S, Kirk S, Gunson R, Bradley-Stewart A, Ainsworth J, Allan S, Anderson J, Babiker A, Chadwick D, Churchill D, Delpech V, Dunn D, Gazzard B, Gilson R, Gompels M, Hay P, Hill T, Johnson M, Jose S, Kegg S, Leen C, Martin F, Mital D, Nelson M, Orkin C, Palfreeman A, Phillips A, Pillay D, Post F, Pritchard J, Sabin CA, Schwenk A, Tariq A, Trevelion R, Ustianowski A, Walsh J, Hill T, Jose S, Phillips A, Sabin CA, Thornton A, Huntington S, Dunn D, Glabay A, Shidfar S, Orkin C, Lynch J, Hand J, de Souza C, Churchill D, Perry N, Tilbury S, Youssef E, Churchill D, Gazzard B, Nelson M, Mabika T, Asboe D, Mandalia S, Anderson J, Munshi S, Post F, Adefisan A, Taylor C, Gleisner Z, Ibrahim F, Campbell L, Chadwick D, Baillie K, Gilson R, Brima N, Williams I, Ainsworth J, Schwenk A, Miller S, Wood C, Johnson M, Youle M, Lampe F, Smith C, Tsintas R, Chaloner C, Hutchinson S, Sabin CA, Phillips A, Hill T, Jose S, Huntington S, Thornton A, Walsh J, Mackie N, Winston A, Weber J, Ramzan F, Carder M, Leen C, Wilson A, Morris S, Gompels M, Allan S, Palfreeman A, Lewszuk A, Kegg S, Faleye A, Ogunbiyi V, Mitchell S, Hay P, Kemble C, Martin F, Russell-Sharpe S, Gravely J, Allan S, Harte A, Tariq A, Spencer H, Jones R, Pritchard J, Cumming S, Atkinson C, Mital D, Edgell V, Allen J, Ustianowski A, Murphy C, Gunder I, Delpech V, Trevelion Ret al., 2019, Virological outcomes of boosted protease inhibitor-based first-line ART in subjects harbouring thymidine analogue-associated mutations as the sole form of transmitted drug resistance, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 74, Pages: 746-753, ISSN: 0305-7453

Journal article

Gossez M, Martin GE, Pace M, Ramjee G, Premraj A, Kaleebu P, Rees H, Inshaw J, Stöhr W, Meyerowitz J, Hopkins E, Jones M, Hurst J, Porter K, Babiker A, Fidler S, Frater J, SPARTAC Trial Investigatorset al., 2019, Virological remission after antiretroviral therapy interruption in female African HIV seroconverters, AIDS, Vol: 33, Pages: 185-197, ISSN: 0269-9370

INTRODUCTION: There are few data on the frequency of virological remission in African individuals after treatment with antiretroviral therapy (ART) in primary HIV infection (PHI). METHODS: We studied participants (n = 82) from South Africa and Uganda in Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion, the first trial of treatment interruption in African individuals with PHI randomized to deferred ART or 48 weeks of immediate ART. All were female and infected with non-B HIV subtypes, mainly C. We measured HIV DNA in CD4 T cells, CD4 cell count, plasma viral load (pVL), cell-associated HIV RNA and T-cell activation and exhaustion. We explored associations with clinical progression and time to pVL rebound after treatment interruption (n = 22). Data were compared with non-African Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion participants. RESULTS: Pretherapy pVL and integrated HIV DNA were lower in Africans compared with non-Africans (median 4.16 vs. 4.72 log10 copies/ml and 3.07 vs. 3.61 log10 copies/million CD4 T cells, respectively; P < 0.001). Pre-ART HIV DNA in Africans was associated with clinical progression (P = 0.001, HR per log10 copies/million CD4 T cells increase (95% CI) 5.38 (1.95-14.79)) and time to pVL rebound (P = 0.034, HR per log10 copies/ml increase 4.33 (1.12-16.84)). After treatment interruption, Africans experienced longer duration of viral remission than non-Africans (P < 0.001; HR 3.90 (1.75-8.71). Five of 22 African participants (22.7%) maintained VL less than 400 copies/ml over a median of 188 weeks following treatment interruption. CONCLUSION: We find evidence of greater probability of virological remission following treatment interruption among African participants, although we are unable to differentiate between sex, ethnicity and viral subtype. The finding warrants further investigation.

Journal article

Viegas EO, Kroidl A, Munseri PJ, Missanga M, Nilsson C, Tembe N, Bauer A, Joachim A, Joseph S, Mann P, Geldmacher C, Fleck S, Stohr W, Scarlatti G, Aboud S, Bakari M, Maboko L, Hoelscher M, Wahren B, Robb ML, Weber J, McCormack S, Biberfeld G, Jani I, Sandstrom E, Lyamuya Eet al., 2018, Optimizing the immunogenicity of HIV prime-boost DNA-MVA-rgp140/GLA vaccines in a phase II randomized factorial trial design, PLOS ONE, Vol: 13, ISSN: 1932-6203

Journal article

Stirrup OT, Dunn DT, Tostevin A, Sabin CA, Pozniak A, Asboe D, Cox A, Orkin C, Martin F, Cane P, Fairbrother K, Fearnhill E, Hubb J, Porter K, Babiker A, Lynch J, Hand J, de Souza C, Churchill D, Perry N, Tilbury S, Youssef E, Clark D, Gazzard B, Nelson M, Mabika T, Mandalia S, Anderson J, Munshi S, Post F, Adefisan A, Taylor C, Gleisner Z, Ibrahim F, Campbell L, Chadwick D, Baillie K, Gilson R, Brima N, Williams I, Ainsworth J, Schwenk A, Miller S, Wood C, Johnson M, Youle M, Lampe F, Smith C, Tsintas R, Chaloner C, Hutchinson S, Phillips A, Hill T, Jose S, Huntington S, Thornton A, Walsh J, Mackie N, Winston A, Weber J, Ramzan F, Carder M, Leen C, Wilson A, Morris S, Gompels M, Allan S, Palfreeman A, Lewszuk A, Kegg S, Faleye A, Ogunbiyi V, Mitchell S, Hay P, Kemble C, Russell-Sharpe S, Gravely J, Allan S, Harte A, Tariq A, Spencer H, Jones R, Pritchard J, Cumming S, Atkinson C, Mital D, Edgell V, Allen J, Ustianowski A, Murphy C, Gunder Iet al., 2018, Risk factors and outcomes for the Q151M and T69 insertion HIV-1 resistance mutations in historic UK data, AIDS Research and Therapy, Vol: 15, ISSN: 1742-6405

Background: The prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial concern in many low and middle-income countries. The Q151M and T69 insertion (T69i) resistance mutations in the viral reverse transcriptase gene can reduce susceptibility to all nucleoside/tide analogue reverse transcriptase inhibitors, motivating the present study to investigate the risk factors and outcomes associated with these mutations. Methods: We considered all data in the UK HIV Drug Resistance Database for blood samples obtained in the period 1997-2014. Where available, treatment history and patient outcomes were obtained through linkage to the UK Collaborative HIV Cohort study. A matched case-control approach was used to assess risk factors associated with the appearance of each of the mutations in ART-experienced patients, and survival analysis was used to investigate factors associated with viral suppression. A further analysis using matched controls was performed to investigate the impact of each mutation on survival. Results: A total of 180 patients with Q151M mutation and 85 with T69i mutation were identified, almost entirely from before 2006. Occurrence of both the Q151M and T69i mutations was strongly associated with cumulative period of virological failure while on ART, and for Q151M there was a particular positive association with use of stavudine and negative association with use of boosted-protease inhibitors. Subsequent viral suppression was negatively associated with viral load at sequencing for both mutations, and for Q151M we found a negative association with didanosine use but a positive association with boosted-protease inhibitor use. The results obtained in these analyses were also consistent with potentially large associations with other drugs. Analyses were inconclusive regarding associations between the mutations and mortality, but mortality was high for pati

Journal article

quinn K, Traboni C, Dily Penchala S, bouliotis G, doyle N, libri V, Khoo S, ashby D, weber J, Nicosia A, Cortese R, Pessi A, Winston Aet al., 2017, A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol., Scientific Reports, Vol: 7, ISSN: 2045-2322

Abstract:Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10mg, 10mg and 20mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was > 72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.

Journal article

White P, Fox J, Weber J, Ward H, Fidler Set al., 2017, HOW MUCH CAN HIV TRANSMISSION BE REDUCED IN HIGH-RISK MSM BY TARGETING TESTING TO DETECT AND TREAT PRIMARY HIV INFECTION (PHI)? ANALYSIS OF A COHORT STUDY USING AN INDIVIDUAL-BASED MODEL, P5.23 How much can hiv transmission be reduced in high-risk msm by targeting testing to detect and treat primary hiv infection (PHI)? analysis of a cohort study using an individual-based model, Publisher: BMJ PUBLISHING GROUP, Pages: A243-A244, ISSN: 1368-4973

Conference paper

Smit E, White E, Clark D, Churchill D, Zhang H, Collins S, Pillay D, Sabin C, Nelson M, Winston A, Jose S, Tostevin A, Dunn DT, UK HIV Drug Resistance Database and the UK Collaborative HIV Cohortet al., 2017, An association between K65R and HIV-1 subtype C viruses in patients treated with multiple NRTIs., Journal of Antimicrobial Chemotherapy, Vol: 72, Pages: 2075-2082, ISSN: 1460-2091

Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis. Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Results: Subtype B patients ( n  =   3410) were mostly MSM (78%) and those with subtype C ( n  =   810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P  <   0.001). Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.

Journal article

Joseph S, Quinn K, Greenwood A, Cope A, McKay P, Hayes P, Kopycinski J, Gilmour J, Miller A, Geldmacher C, Nadai Y, Ahmed M, Montefiori D, Dally L, Bouliotis G, Lewis D, Tatoud R, Wagner R, Esteban M, Shattock R, McCormack S, Weber Jet al., 2017, A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 protein/adjuvant HIV vaccines in two immunization regimes, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The ap

Journal article

Herath S, Le Heron A, Colloca S, Patterson S, Tatoud R, Weber J, Dickson Get al., 2016, Strain-dependent and distinctive T-cell responses to HIV antigens following immunisation of mice with differing chimpanzee adenovirus vaccine vectors, Vaccine, Vol: 34, Pages: 4378-4385, ISSN: 1873-2518

In vivo vaccination studies are conventionally conducted in a single mouse strain with results, only reflecting responses to a single immunogenetic background. We decided to examine the immune response to an HIV transgene (gag, pol and nef fusion protein) in 3 strains of mice (CBA, C57BL/6 and BALB/c) to determine the spectrum of responses and in addition to determine whether the serotype of the adenoviral vector used (ChAd3 and ChAd63) impacted the outcome of response. Our results demonstrated that all three strains of mice responded to the transgene and that the magnitude of responses were different between the strains. The C57BL/6 strain showed the lowest range of responses compared to the other strains and, very few responses were seen to the same peptide pool in all three strains of mice. In CBA and BALB/c mice there were significant differences in IFNγ production dependent on the adenoviral vector used. Our results suggest that employing a single strain of mouse may underestimate the efficacy and efficiency of vaccine products.

Journal article

Hoffmann M, Pantazis N, Martin GE, Hickling S, Hurst J, Meyerowitz J, Willberg CB, Robinson N, Brown H, Fisher M, Kinloch S, Babiker A, Weber J, Nwokolo N, Fox J, Fidler S, Phillips R, Frater J, SPARTAC and CHERUB Investigatorset al., 2016, Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection, PLOS Pathogens, Vol: 12, ISSN: 1553-7366

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.

Journal article

Martin GE, Pantazis N, Hoffmann M, Hickling S, Hurst J, Meyerowitz J, Willberg CB, Robinson N, Brown H, Fisher M, Kinloch S, Babiker A, Weber J, Nwokolo N, Fox J, Fidler S, Phillips R, Frater Jet al., 2016, Exhaustion of activated CD8 T cells predicts disease progression in primary HIV-1 infection, Journal of the International AIDS Society, Vol: 19, Pages: 32-32, ISSN: 1758-2652

Journal article

Joachim A, Bauer A, Joseph S, Geldmacher C, Munseri PJ, Aboud S, Missanga M, Mann P, Wahren B, Ferrari G, Polonis VR, Robb ML, Weber J, Tatoud R, Maboko L, Hoelscher M, Lyamuya EF, Biberfeld G, Sandström E, Kroidl A, Bakari M, Nilsson C, McCormack Set al., 2016, Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial., PLOS One, Vol: 11, ISSN: 1932-6203

BACKGROUND: A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA). METHODS: Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart. RESULTS: The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding antibodies to subtype C Env (included in HIV-DNA and protein boost), subtype B Env (included only in HIV-DNA) and CRF01_AE Env (included only in HIV-MVA) were significantly boosted by the CN54rgp140/GLA-AF immunizations. Functional antibodies detected using an infectious molecular clone virus/peripheral blood mononuclear cell neutralization assay, a pseudovirus/TZM-bl neutralization assay or by assays for antibody-dependent cellular cytotoxicity (ADCC) were not significantly boosted. In contrast, T-cell proliferative responses to subtype B MN antigen and IFN-γ ELISpot responses to Env peptides were significantly enhanced. Four volunteers not primed with HIV-DNA and HIV-MVA before the CN54rgp140/GLA-AF immunizations mounted an antibody response, while cell-mediated responses were rare. After the two Env subtype C protein immunizations, a trend towards higher median subtype C Env binding antibody titers was found in vaccinees who had received HIV-DN

Journal article

Thornhill J, Inshaw J, Kaleebu P, Cooper D, Ramjee G, Schechter M, Tambussi G, Fox J, Samuel M, Miro JM, Weber J, Porter K, Fidler Set al., 2016, Enhanced normalisation of CD4/CD8 ratio with earlier antiretroviral therapy at Primary HIV Infection., Journal of Acquired Immune Deficiency Syndromes, Vol: 73, Pages: 69-73, ISSN: 0894-9255

BACKGROUND: Total CD4 T-cell counts predict HIV disease progression, but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker of immune dysfunction, a prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite ART, recovery of CD4/CD8 ratio in chronic HIV infection is incomplete; we hypothesize enhanced CD4/CD8 ratio recovery with earlier treatment initiation in recently infected individuals. METHODS: CD4 count and CD4/CD8 ratio were analyzed using data from two cohorts: SPARTAC trial, and the UK HIV Seroconverters Cohort where Primary HIV infection (PHI) was defined as within 6 months from estimated date of infection. Using time-to-event methods and Cox proportional hazard models we examined the effect of CD4/CD8 ratio at seroconversion on disease progression (CD4<350 cells/mm/ART initiation), and factors associated with time from ART initiation to CD4/CD8 normalization (ratio >1.0). FINDINGS: Of 573 seroconverters, 482 (84%) had abnormal CD4/CD8 ratios at HIV seroconversion. Individuals with higher CD4/CD8 ratio at seroconversion were significantly less likely to reach the disease progression end point (aHR [95% CI] = 0.52 [0.32, 0.82], p=0.005). The longer the interval between seroconversion and ART initiation (HR [95% CI] =0.98 per month increase [0.97, 0.99], p<0.001) the less likely CD4/CD8 ratio normalization. ART initiation within 6 months from seroconversion was significantly more likely to normalize (HR [95% CI] =2.47 [1.67, 3.67], p<0.001) than those initiating later. INTERPRETATION: The majority of individuals presenting in PHI have abnormal CD4/CD8 ratios. The sooner ART is initiated in PHI the greater the probability of achieving normal CD4/CD8 ratio.

Journal article

Quinn K, Bouliotis G, Doyle N, Winston A, Ashby D, Weber J, Libri V, Amara A, Back D, Penchala SD, Khoo S, Nelson M, Jones R, Cortese R, Pessi Aet al., 2016, A first-in-human study, in HIV-positive men, of the novel HIV-fusion inhibitor C34-PEG4-Chol, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 18-18, ISSN: 1464-2662

Conference paper

May MT, Gill MJ, Wittkop L, Klein M, Sabin C, Harrigan PR, Dunn D, Vehreschild JJ, Rubio R, Mocroft A, Cavassini M, Reiss P, Monforte AD, Zangerle R, Ingle SM, Hill T, Jose S, Sterne JAC, Boulle A, Stephan C, Miro JM, Cavassini M, Chene G-V, Costagliola D, Dabis F, Monforte AD, del Amo J, Van Sighem A, Vehreschild J, Gill J, Guest J, Haerry DH-U, Hogg R, Justice A, Mocroft A, Obel N, Crane H, Smith C, Reiss P, Saag M, Sterling T, Teira R, Williams M, Zangerle R, Sterne J, May M, Ingle S, Trickey A, Ainsworth J, Anderson J, Babiker A, Chadwick D, Delpech V, Dunn D, Fisher M, Gazzard B, Gilson R, Hay P, Gompels M, Hill T, Johnson M, Jose S, Kegg S, Leen C, Mackie N, Nelson M, Orkin C, Palfreeman A, Phillips A, Pillay D, Post F, Sabin C, Sachikonye M, Schwenk A, Walsh J, Thornton A, Huntington S, Glabay A, Orkin C, Garrett N, Lynch J, Hand J, de Souza C, Fisher M, Perry N, Tilbury S, Youssef E, Churchill D, Gazzard B, Nelson M, Waxman M, Asboe D, Mandalia S, Anderson J, Munshi S, Awosika D, Post F, Korat H, Taylor C, Gleisner Z, Ibrahim F, Campbell L, Babiker A, Dunn D, Glabay A, Chadwick D, Baillie K, Cope E, Gibney M, Gibson J, Gilson R, Brima N, Williams I, Ainsworth J, Schwenk A, Miller S, Wood C, Johnson M, Youle M, Lampe F, Smith C, Chaloner C, Hill T, Huntington S, Jose S, Phillips A, Sabin C, Thornton A, Walsh J, Mackie N, Winston A, Weber J, Ramzan F, Carder M, Leen C, Wilson A, Morris S, Gompels M, Allan S, Palfreeman A, Moore A, Fox L, Bojanowski J, Lewszuk A, Kegg S, Main P, Mitchell D, Hunter D, Sachikonye M, Hay P, Dhillon M, Martin F, Douglas S, Russell-Sharp Set al., 2016, Mortality of treated HIV-1 positive individuals according to viral subtype in Europe and Canada: collaborative cohort analysis, AIDS, Vol: 30, Pages: 503-513, ISSN: 0269-9370

Objectives: To estimate prognosis by viral subtype in HIV-1-infected individuals fromstart of antiretroviral therapy (ART) and after viral failure.Design: Collaborative analysis of data from eight European and three Canadiancohorts.Methods: Adults (N>20 000) who started triple ART between 1996 and 2012 andhad data on viral subtype were followed for mortality. We estimated crude andadjusted (for age, sex, regimen, CD4þ cell count, and AIDS at baseline, period ofstarting ART, stratified by cohort, region of origin and risk group) mortality hazardratios (MHR) by subtype. We estimated MHR subsequent to viral failure defined astwo HIV-RNA measurements greater than 500 copies/ml after achieving viralsuppression.Results: The most prevalent subtypes were B (15 419; 74%), C (2091; 10%), CRF02AG(1057; 5%), A (873; 4%), CRF01AE (506; 2.4%), G (359; 1.7%), and D (232; 1.1%).Subtypes were strongly patterned by region of origin and risk group. During 104 649person-years of observation, 1172/20 784 patients died. Compared with subtype B,mortality was higher for subtype A, but similar for all other subtypes. MHR for A versus Bwere 1.13 (95% confidence interval 0.85,1.50) when stratified by cohort, increased to1.78 (1.27,2.51) on stratification by region and risk, and attenuated to 1.59 (1.14,2.23)on adjustment for covariates. MHR for A versus B was 2.65 (1.64,4.28) and 0.95(0.57,1.57) for patients who started ART with CD4þ cell count below, or more than, 100cells/ml, respectively. There was no difference in mortality between subtypes A, B and Cafter viral failure.Conclusion: Patients with subtype A had worse prognosis, an observation which maybe confounded by socio-demographic factors.

Journal article

Herath S, Le Heron A, Colloca S, Bergin P, Patterson S, Weber J, Tatoud R, Dickson Get al., 2015, Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag–pol–nef antigen, Vaccine, Vol: 33, Pages: 7283-7289, ISSN: 1873-2518

Journal article

Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, Meyerowitz J, Willberg C, Koelsch KK, Robinson N, Brown H, Fisher M, Kinloch S, Cooper DA, Schechter M, Tambussi G, Fidler S, Babiker A, Weber J, Kelleher AD, Phillips RE, Frater Jet al., 2015, Immunological biomarkers predict HIV-1 viral rebound after treatment interruption, Nature Communications, Vol: 6, ISSN: 2041-1723

Journal article

Hoehn KB, Gall A, Bashford-Rogers R, Fidler SJ, Kaye S, Weber JN, McClure MO, Kellam P, Pybus OGet al., 2015, Dynamics of immunoglobulin sequence diversity in HIV-1 infected individuals, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 370, ISSN: 0962-8436

Journal article

Jose S, Quinn K, Dunn D, Cox A, Sabin C, Fidler Set al., 2015, Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation, HIV Medicine, Vol: 17, Pages: 368-372, ISSN: 1464-2662

ObjectivesNo randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development.MethodsIn a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART.ResultsOf 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL.ConclusionsWe found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL.

Journal article

Hamlyn E, Stoehr W, Cooper DA, Fisher M, Tambussi G, Schechter M, Miro JM, Vanobberghen F, Babiker A, Weber J, Mcclure M, Porter K, Fidler Set al., 2015, The effect of short-course antiretroviral therapy initiated in primary HIV-1 infection on interleukin-6 and D-dimer levels, AIDS, Vol: 29, Pages: 1355-1361, ISSN: 0269-9370

Objective: Interruption of antiretroviral therapy (ART) in chronic HIV disease is associated with increased mortality, predicted by elevations in interleukin-6 (IL-6) and D-dimer. The effect of ART interruption in primary HIV-1 infection on these biomarkers is unknown.Methods: Plasma samples from 200 HIV seroconverters enrolled in the Short Pulse Anti-Retroviral Therapy At HIV Seroconversion trial of deferred ART (standard of care) – 12 or 48 week ART (ART12 or ART48, respectively) – were analysed for IL-6 and D-dimer at weeks 0, 12, 16, 48, 52, 60 and 108 after randomization. Changes in log10 levels from weeks 0 to 12 were analysed using linear regression, as were changes from baseline to 4 weeks after stopping ART. Areas under the biomarker–time curves (AUC) to week 108 were adjusted for baseline values, and compared across all arms.Results: Median (inter-quartile range) baseline IL-6 and D-dimer were 1.45 (0.88, 2.41) pg/ml and 0.34 (0.20, 0.50) mg/l, respectively. At week 12, D-dimer levels were significantly lower among treated compared to untreated individuals (P < 0.001), whereas IL-6 levels were similar (P = 0.23). Within 4 weeks from stopping ART, IL-6 and D-dimer levels rose by 22 and 18%, reaching pre-ART levels. Over 108-week follow-up, there was no difference between arms in IL-6 AUC (P = 0.53), but D-dimer AUC was significantly lower for ART12 and ART48 compared to standard of care (overall P = 0.008).Conclusion: Stopping ART in primary HIV-1 infection leads to inflammatory biomarker rebound to pre-treatment levels. However, over 108-week follow-up, we found no evidence that biomarker levels were higher for those interrupting ART, compared to those remaining ART-naïve, and D-dimer levels were significantly lower.

Journal article

Huntington S, Thorne C, Newell M-L, Anderson J, Taylor GP, Pillay D, Hill T, Tookey PA, Sabin Cet al., 2015, Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy, AIDS, Vol: 29, Pages: 801-809, ISSN: 0269-9370

Journal article

Knudsen ML, Ljungberg K, Tatoud R, Weber J, Esteban M, Liljestrom Pet al., 2015, Alphavirus Replicon DNA Expressing HIV Antigens Is an Excellent Prime for Boosting with Recombinant Modified Vaccinia Ankara (MVA) or with HIV gp140 Protein Antigen, PLOS One, Vol: 10, ISSN: 1932-6203

Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells andantibodies. Studies in humans have shown that DNA vaccines are safe, but their immuno-genicity needs further improvement. As a step towards this goal, we have previously dem-onstrated that immunogenicity is increased with the use of an alphavirus DNA-launchedreplicon (DREP) vector compared to conventional DNA vaccines. In this study, we investi-gated the effect of varying the dose and number of administrations of DREP when given asa prime prior to a heterologous boost with poxvirus vector (MVA) and/or HIV gp140 proteinformulated in glucopyranosyl lipid A (GLA-AF) adjuvant. The DREP and MVA vaccine con-structs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three ad-ministrations of 0.2μg DREP induced lower HIV-specific T cell and IgG responses than theequivalent number of immunizations with 10μg DREP. However, the two doses were equal-ly efficient as a priming component in a heterologous prime-boost regimen. The magnitudeof immune responses depended on the number of priming immunizations rather than thedose. A single low dose of DREP prior to a heterologous boost resulted in greatly increasedimmune responses compared to MVA or protein antigen alone, demonstrating that a mere0.2μg DREP was sufficient for priming immune responses. Following a DREP prime, T cellresponses were expanded greatly by an MVA boost, and IgG responses were also expand-ed when boosted with protein antigen. When MVA and protein were administered simulta-neously following multiple DREP primes, responses were slightly compromised comparedto administering them sequentially. In conclusion, we have demonstrated efficient primingof HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the prim-ing effect depends on number of primes administered rather than dose.

Journal article

Roberts HE, Hurst J, Robinson N, Brown H, Flanagan P, Vass L, Fidler S, Weber J, Babiker A, Phillips RE, McLean AR, Frater J, SPARTAC trial investigatorset al., 2015, Structured observations reveal slow HIV-1 CTL escape., Plos Genetics, Vol: 11, Pages: e1004914-e1004914, ISSN: 1553-7404

The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL escape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN-γ ELISpot and longitudinal HIV-1 gag, pol, and nef sequence data were used to study the timing and prevalence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero respectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two years.

Journal article

White PJ, Fox J, Weber J, Fidler S, Ward Het al., 2014, How Many HIV Infections May Be Averted by Targeting Primary Infection in Men Who Have Sex With Men? Quantification of Changes in Transmission-Risk Behavior, Using an Individual-Based Model, Journal of Infectious Diseases, Vol: 210, Pages: S594-S599, ISSN: 1537-6613

In the United Kingdom, human immunodeficiency virus (HIV) transmission among men who have sex with men(MSM) is not under control, despite readily available treatment, highlighting the need to design a cost-effectivecombination prevention package. MSM report significantly reduced transmission risk behavior following HIVdiagnosis. To assess the effectiveness of HIV diagnosis in averting transmission during highly infectious primaryHIV infection (PHI), we developed a stochastic individual-based model to calculate the number of HIVtransmissionevents expected to occur from a cohort of recently infected MSM with and those without the behaviorchanges reported after diagnosis. The model incorporates different types of sex acts, incorporates condom use,and distinguishes between regular and casual sex partners. The impact on transmission in the 3 months afterinfection depends on PHI duration and testing frequency. If PHI lasts for 3 months and testing is performedmonthly, then behavior changes after diagnosis would have reduced estimated transmission events by 49%–52%,from 31–45 to 15–23 events; a shorter duration of PHI and/or a lower testing frequency reduces the number ofinfections averted. Diagnosing HIV during PHI can markedly reduce transmission by changing transmissionriskbehavior. Because of the high infectivity but short duration of PHI, even short-term behavior change cansignificantly reduce transmission. Our quantification of the number of infections averted is an essential componentof assessment of the cost-effectiveness of strategies to increase detection and diagnoses of PHI.

Journal article

Thornhill J, Inshaw J, Oomeer S, Kaleebu P, Cooper D, Ramjee G, Schechter M, Tambussi G, Fox J, Maria Miro J, Weber J, Babiker A, Porter K, Fidler Set al., 2014, Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection, Journal of the International AIDS Society, Vol: 17, ISSN: 1758-2652

Introduction: Despite normalization of total CD4 counts, ongoing immune dysfunction is noted amongst those on antiretroviraltherapy (ART). Low CD4/CD8 ratio is associated with a high risk of AIDS and non-AIDS events and may act as a marker of immunesenescence [1]. This ratio is improved by ART although normalization is uncommon (7%) [2]. The probability of normalizationof CD4 count is improved with immediate ART initiation in primary HIV infection (PHI) [3]. We examined whether CD4/CD8 ratiosimilarly normalized in immediate vs. deferred ART at PHI.Methods: Using data from the SPARTAC trial and the UK Register of HIV Seroconverters, we examined the effect of ART withtime (continuous) from HIV seroconversion (SC) on CD4/CD8 ratio (]1) adjusted for sex, risk group, ethnicity, enrolment froman African site and both CD4 count and age at ART initiation. We also examined that effect by dichotomizing HIV duration at ARTinitiation (ART started within six months of SC: early ART; ART initiatedsix months after SC: deferred). We also considered timeto CD4 count normalization (]900 cells/mm3).Results: In total, 353 initiated ART with median (IQR) 97.9 (60.5, 384.5) days from estimated seroconversion; 253/353 early ART,100 deferred ART. At one year after starting ART, 114/253 (45%) early ART had normalized CD4/8 ratio, compared with 11/99(11%) in the deferred group, whilst 83/253 (33%) of early ART had normalized CD4 counts, compared with 3/99 (3%) in thedeferred group. Individuals initiating within six months of PHI were significantly more likely to reach normal ratio than thoseinitiating later (HR, 95% CI 2.96, 1.755.01, pB0.001). The longer after SC ART was initiated, the reduced likelihood of achievingnormalization of CD4/CD8 ratio (HR 0.98, 95% CI 0.960.99 for each 30-day increase). CD4 count at ART initiation was alsoassociated with normalization, as expected (HR 1.002, 95% CI 1.0011.002, pB0.001). There was an association betweennormal CD4/CD8 ratio and being virally suppr

Journal article

The HIV-CAUSAL Collaboration, 2014, Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries, AIDS, Vol: 28, Pages: 2461-2473, ISSN: 0269-9370

Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis.Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, had CD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting.Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90–1.63) for tuberculosis, 2.61 (1.05–6.49) for MAC, 1.17 (0.34–4.08) for CMV retinitis, 1.18 (0.62–2.26) for PML, 1.21 (0.83–1.75) for HSV, 1.18 (0.87–1.58) for Kaposi sarcoma, 1.56 (0.82–2.95) for NHL, 1.11 (0.56–2.18) for cryptococcosis and 0.77 (0.40–1.49) for candidiasis.Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries.

Journal article

Williams JP, Hurst J, Stoehr W, Robinson N, Brown H, Fisher M, Kinloch S, Cooper D, Schechter M, Tambussi G, Fidler S, Carrington M, Babiker A, Weber J, Koelsch KK, Kelleher AD, Phillips RE, Frater Jet al., 2014, HIV-1 DNA predicts disease progression and post-treatment virological control., ELIFE, Vol: 3, ISSN: 2050-084X

Journal article

Hamlyn E, Fidler S, Stoehr W, Cooper DA, Tambussi G, Schechter M, Miro JM, Mcclure M, Weber J, Babiker A, Porter Ket al., 2014, Interleukin-6 and D- dimer levels at seroconversion as predictors of HIV-1 disease progression, AIDS, Vol: 28, Pages: 869-874, ISSN: 0269-9370

Journal article

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