48 results found
Thornhill J, Orkin C, 2021, Long-acting injectable HIV therapies: the next frontier, CURRENT OPINION IN INFECTIOUS DISEASES, Vol: 34, Pages: 8-15, ISSN: 0951-7375
Thornhill J, Dufaur L, Parry S, et al., 2020, Use of immediate ART in late HIV presenters is feasible and efficacious in groups beyond MSM, Publisher: WILEY, Pages: 22-23, ISSN: 1464-2662
Gupta RK, Peppa D, Hill AL, et al., 2020, Evidence for HIV-1 cure after CCR5 Delta 32/Delta 32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report, LANCET HIV, Vol: 7, Pages: E340-E347, ISSN: 2352-3018
Martin GE, Pace M, Shearer FM, et al., 2020, Levels of human immunodeficiency virus DNA are determined before ART initiation and linked to CD8 T-Cell activation and memory expansion, Journal of Infectious Diseases, Vol: 221, Pages: 1135-1145, ISSN: 0022-1899
Initiation of antiretroviral therapy (ART) in early compared with chronic human immunodeficiency virus (HIV) infection is associated with a smaller HIV reservoir. This longitudinal analysis of 60 individuals who began ART during primary HIV infection (PHI) investigates which pre- and posttherapy factors best predict HIV DNA levels (a correlate of reservoir size) after treatment initiation during PHI. The best predictor of HIV DNA at 1 year was pre-ART HIV DNA, which was in turn significantly associated with CD8 memory T-cell differentiation (effector memory, naive, and T-bet−Eomes− subsets), CD8 T-cell activation (CD38 expression) and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) expression on memory T cells. No associations were found for any immunological variables after 1 year of ART. Levels of HIV DNA are determined around the time of ART initiation in individuals treated during PHI. CD8 T-cell activation and memory expansion are linked to HIV DNA levels, suggesting the importance of the initial host-viral interplay in eventual reservoir size.
Fidler S, Stӧhr W, Pace M, et al., 2020, A randomized comparison of antiretroviral therapy alone versus antiretroviral therapy with a 'kick-and-kill' approach, on measures of the HIV reservoir amongst participants with recent HIV infection: the RIVER trial, The Lancet, Vol: 395, Pages: 888-898, ISSN: 0140-6736
Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing - termed ‘kick and kill’ - have been explored as a strategy towards an HIV cure. RIVER is the first randomized trial to determine the impact of ART alone versus ART plus ‘kick-and-kill’ on markers of the HIV reservoir.Methods: RIVER (Trial registration: NCT02336074) was an open-label, multicenter, 1:1 randomized controlled trial of ART-only (control) versus ART plus the histone deacetylase inhibitor vorinostat (the ‘kick’) and replication-deficient viral vector vaccines encoding conserved HIV sequences ChAdV63.HIVconsv-prime, MVA.HIVconsv-boost T-cell vaccination (the ‘kill’) (ART+V+V; intervention) in HIV-positive adults treated in recent HIV-infection. The primary endpoint was total HIV DNA in peripheral blood CD4+ T-cells at weeks 16 and 18 post-randomization. Secondary endpoints included safety, alternative measures of the HIV reservoir including quantitative viral outgrowth, HIV-specific T-cell frequencies, and CD8+ T-cell mediated viral inhibition.Findings: Between December 2015 and November 2017, 60 HIV-positive male participants were randomized (computer-based and stratified by time since diagnosis; 30 participants in each trial arm) and completed the study interventions, with no loss-to-follow-up. There were no intervention-related serious adverse events. Mean total HIV DNA at weeks 16 and 18 was 3.02 log10 copies HIV DNA/106 CD4+ T-cells in the control and 3.06 log10 copies HIV DNA/106 CD4+ T-cells in the intervention arm, with no statistically significant difference (mean difference of 0.04 (95%CI -0.03, 0.11) log10 total HIV DNA copies/106 CD4+ T-cells (p=0.26)). Interpretation: This ‘kick-and-kill’ approach conferred no significant benefit compared to ART alone on measures of
Thornhill J, Lynch K, Skelton J, et al., 2019, Vedolizumab use and the associations between α4β7 expression and HIV reservoir in the gut during treated primary HIV infection, AIDS, Vol: 33, Pages: 2268-2271, ISSN: 0269-9370
Latent HIV infection in gut CD4+ cells is a barrier to HIV eradication. α4β7 integrin is a gut homing marker expressed on CD4+ cells. Monoclonal antibodies against α4β are being trialled to induce HIV remission. Using gut biopsy samples taken from a cohort of HIV+ individuals treated during primary HIV infection, we characterised β7 expression and HIV DNA in terminal ileum and rectum. We demonstrate an association between HIV DNA and β7 expression in gut, and present the case of a HIV+ individual treated with an α4β7 antibody; finding no evidence of HIV remission by humanized murine viral outgrowth assay.
Thornhill JP, Carolina H, Lewis H, et al., 2019, HIV reservoir in gut from PHI treated individuals is stable over time and correlates with blood markers of HIV reservoir and inflammation- findings from the HEATHER gut study, Publisher: WILEY, Pages: 40-42, ISSN: 1464-2662
Thornhill J, Pace M, Genevieve M, et al., 2019, CD32 expressing doublets in HIV infected gut-associated lymphoid are associated with a T follicular helper cell phenotype, Mucosal Immunology, Vol: 12, Pages: 1212-1219, ISSN: 1933-0219
Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell–T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + individuals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one individual. As previously shown for blood, CD32high CD4 cells were mainly doublets of CD4 T cells and B cells, with T-cell expression of ICOS in tonsil and gut tissue. CD4 T cells associated with CD32 (compared with ‘CD32−' CD4 cells) had higher expression of follicular markers CXCR5, PD-1, ICOS, and Bcl-6 consistent with a T follicular helper (TFH) phenotype. There was a significant correlation between rectal HIV DNA levels and CD32 expression on TFH cells. Together, these data suggest that CD32high doublets are primarily composed of TFH cells, a subset known to be preferentially infected by HIV.
Thornhill J, Pace M, Martin G, et al., 2019, CD32 expression identifies B cell-T cell doublets in gut-associated lymphoid tissue that are enriched for T follicular helper cells but not for HIV DNA, Publisher: WILEY, Pages: 24-25, ISSN: 1464-2662
Thornhill J, Flanagan S, Moir K, et al., 2019, The East London Immediate ART (ELIA) survey: attitudes and barriers to immediate ART initiation, Publisher: WILEY, Pages: 71-72, ISSN: 1464-2662
Thornhill J, Herrera C, Hoare J, et al., 2019, The impact of vorinostat and therapeutic vaccine on gut HIV DNA: the RIVER gut study, Publisher: WILEY, Pages: 7-7, ISSN: 1464-2662
Lwanga J, Martin G, Hamzah L, et al., 2019, The effect of time to viral suppression at primary HIV infection on long-term immunological recovery: results from the HEATHER cohort, Publisher: WILEY, Pages: 7-8, ISSN: 1464-2662
Seers T, Vassallo P, Pollock KM, et al., 2018, CD4/CD8 ratio in children with perinatally acquired HIV-1 infection, HIV Medicine, Vol: 19, Pages: 668-672, ISSN: 1464-2662
BackgroundIn adults with horizontally acquired HIV an inverted CD4/CD8 ratio is associated with persistent immune activation, size of HIV reservoir and predicts an increased risk of non-AIDS adverse events. Normalisation of this ratio with antiretroviral therapy (ART) is sub-optimal in adults, despite viral suppression, and is less well described in paediatric populations. We investigated rates of CD4/CD8 ratio recovery in children with perinatally-acquired HIV (PaHIV) on ART.MethodsCross-sectional, retrospective analysis of routine clinical data in children with PaHIV (5-18yrs) attending a single UK centre. ResultsCD4/CD8 normalisation was seen in 62% of children on suppressive ART. A negative correlation was found between current CD4/CD8 ratio and age at start of ART. Positive correlations were found between current CD4/CD8 ratio and total time with suppressed HIV viral load, and nadir CD4 counts. Multiple linear regression analysis showed that age at start of ART was significantly associated with current CD4/CD8 ratio (standardised β -0.680, p<0.001). Patient sex, ethnicity and antiretroviral regimen did not affect ratio recovery.ConclusionsWe found higher rates of CD4/CD8 ratio normalisation compared to previous adult studies. Children who started ART at a younger age were more likely to recover a normal ratio. The current policy of universal treatment for all HIV-positive adults and children will enhance immunological normalisation.
Thornhill JP, Martin GE, Hoare J, et al., 2018, Follicular CD8+T-cells in gut-associated lymphoid tissue are associated with lower HIV-1 reservoir in the terminal ileum after ART initiated during primary HIV infection, Publisher: JOHN WILEY & SONS LTD, Pages: 96-96
Martin GE, Pace M, Thornhill JP, et al., 2018, CD32-Expressing CD4 T Cells are phenotypically diverse and can contain proviral HIV DNA, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low, CD32+CD14+, and CD32high). Of note, CD4 negative enrichment kits remove the majority of CD4+CD32+ T cells, potentially skewing subsequent analyses if used. CD32high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3+CD4+CD32+ phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32+ T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations.
Thornhill J, Hoare J, Peake S, et al., 2018, Two case reports on safety and impact of alpha 4 beta 7 integrin monoclonal antibody in treated primary HIV infection on HIV reservoirs OVERRIDE, Publisher: WILEY, Pages: S41-S41, ISSN: 1464-2662
Thornhill J, Martin G, Pace M, et al., 2018, CD32 is enriched on CD4(+) T-cells with a T-follicular, Publisher: WILEY, Pages: S10-S10, ISSN: 1464-2662
Fidler S, Lewis H, Meyerowitz J, et al., 2017, A pilot evaluation of whole blood finger-prick sampling for point-of-care HIV viral load measurement: the UNICORN study., Scientific Reports, Vol: 7, ISSN: 2045-2322
There is a global need for HIV viral load point-of-care (PoC) assays to monitor patients receiving antiretroviral therapy. UNICORN was the first study of an off-label protocol using whole blood finger-prick samples tested with and without a simple three minute spin using a clinic-room microcentrifuge. Two PoC assays were evaluated in 40 HIV-positive participants, 20 with detectable and 20 with undetectable plasma viral load (pVL) (<20 copies/ml). Using 100 µl finger-prick blood samples, the Cepheid Xpert HIV-1 Viral Load and HIV-1 Qual cartridges were compared with laboratory pVL assessment (TaqMan, Roche). For participants with undetectable viraemia by TaqMan, there was poor concordance without centrifugation with the TaqMan platform with only 40% 'undetectable' using Xpert VL and 25% 'not detected' using the Qual assay. After a 3 minute spin, 100% of samples were undetectable using either assay, showing full concordance with the TaqMan assay. Defining a lower limit of detection of 1000 copies/ml when including a spin, there was 100% concordance with the TaqMan platform with strong correlation (rho 0.95 and 0.94; p < 0.0001 for both assays). When including a simple microcentrifugation step, finger-prick PoC testing was a quick and accurate approach for assessing HIV viraemia, with excellent concordance with validated laboratory approaches.
Martin GE, Pace M, Thornhill JP, et al., 2017, Enrichment of the HIV reservoir in CD32+ CD4 T cells occurs early in blood and tissue
<jats:title>Abstract</jats:title><jats:p>The Fc receptor CD32 has been proposed as a marker for CD4 T cells latently infected with HIV. We demonstrate that enrichment for HIV DNA in CD32+ CD4 T cells can be found early in infection in both tissue and blood. However, we find no evidence for a correlation between CD32 expression on CD4 T cells and either HIV DNA levels or time to rebound viraemia following treatment interruption. CD32+ CD4 T cells have a more differentiated memory phenotype, and high levels of expression of immune checkpoint receptors PD-1, Tim-3 and TIGIT as well as the activation marker, HLA DR. There was no difference in the phenotype or frequency of CD32 expressing cells prior to or after the initiation of antiretroviral therapy, or compared with healthy controls, suggesting that preferential infection or survival, rather than up-regulation, may be responsible for the observed enrichment of proviral HIV DNA in CD32+ CD4 T cells.</jats:p>
Martin GE, Pace M, Thornhill JP, et al., 2017, Enrichment of the HIV reservoir in CD32+CD4 T cells occurs early and is closely associated with immune checkpoint receptor expression, Publisher: JOHN WILEY & SONS LTD, Pages: 103-103
Thornhill J, Herrera C, Olejniczak N, et al., 2017, Impact of ART in primary HIV infection on T cell immune exhaustion in gut-associated lymphoid tissue: implications for HIV persistence, Publisher: WILEY, Pages: 6-6, ISSN: 1464-2662
Thornhill J, Fidler S, Martin G, et al., 2017, Diagnosis of primary HIV infection with rapid ART in the HEATHER cohort: towards zero infections, Publisher: WILEY, Pages: 23-24, ISSN: 1464-2662
Fidler S, Olson AD, Bucher HC, et al., 2017, Virological Blips and Predictors of Post Treatment Viral Control After Stopping ART Started in Primary HIV Infection., Journal of Acquired Immune Deficiency Syndromes, Vol: 74, Pages: 126-133
Background: Few individuals commencing antiretroviral therapy (ART) in primary HIV infection (PHI) maintain undetectable viremia after treatment cessation. Associated factors remain unclear given the importance of the phenomenon to cure research.Methods: Using CASCADE data of seroconverters starting ART in PHI (≤6 months from seroconversion), we estimated proportions experiencing viral blips (>400 copies followed by <400 copies HIV-RNA/mL without alteration of regimen) while on ART. We used Cox models to examine the association between time from ART stop to loss of control (2 consecutive measurements >1000 copies per milliliter) and magnitude and frequency of blips while on ART, time from seroconversion to ART, time on ART, adjusting for mean number of HIV-RNA measurements/year while on ART, and other confounders.Results: Seven hundred seventy-eight seroconverters started ART in PHI with ≥3 HIV-RNA measurements. Median interquartile range (IQR) ART duration was 16.2 (8.0–35.9) months, within which we observed 13% with ≥1 blip. Of 228 who stopped ART, 119 rebounded; time to loss of control was associated with longer interval between seroconversion and ART initiation [hazard ratio (HR) = 1.16 per month; 1.04, 1.28], and blips while on ART (HR = 1.71 per blip; 95% confidence interval = 0.94 to 3.10). Longer time on ART (HR = 0.84 per additional month; 0.76, 0.92) was associated with lower risk of losing control. Of 228 stopping ART, 22 (10%) maintained post treatment control (PTC), ie, HIV-RNA <50 copies per milliliter ≥24 months after ART cessation.Conclusion: HIV viral blips on therapy are associated with subsequent viral rebound on stopping ART among individuals treated in PHI. Longer duration on ART is associated with a greater chance of PTC.
Thornhill JP, Fidler S, Klenerman P, et al., 2017, The role of CD4+T follicular helper cells in HIV infection: from the germinal center to the periphery, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
T follicular helper cells (TFh) are key components of the adaptive immune system; they are primarily found in germinal centers (GCs) where their interaction with B cells supports humoral immune responses and efficient antibody production. They are defined by the expression of CXC receptor 5, program death-1, ICOS, and secretion of IL-21. Their differentiation is regulated by B-cell lymphoma 6. The relationship and function of circulating TFh to bona fide TFh resident in the GC is much debated. HIV infection impacts the TFh response with evidence of aberrant TFh function observed in acute and chronic infection. Effective TFh responses are associated with the development of broadly neutralizing antibody responses to HIV and may be important for viral control. In addition, TFh are preferentially infected and act as a key reservoir for latent HIV infection. This review explores recent developments in our understanding of TFh differentiation, regulation, function, and the relationship between cTFh and those in GCs, and the complex interaction between TFh and HIV infection.
Thornhill J, Inshaw J, Kaleebu P, et 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.
Thornhill J, Underwood J, Kuldanek K, et al., 2016, Impact of timing of ART on HIV DNA; findings from HEATHER, an observational cohort study, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 11-11, ISSN: 1464-2662
Hurst J, Hoffmann M, Pace M, et al., 2015, Immunological biomarkers predict HIV-1 viral rebound after treatment interruption, Nature Communications, Vol: 6, Pages: 1-9, ISSN: 2041-1723
Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of ‘post-treatment control’ (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication.
Fidler S, Thornhill J, Malatinkova E, et al., 2015, IAS Towards an HIV Cure Symposium: people focused, science driven: 18-19 July 2015, Vancouver, Canada., Journal of virus eradication, Vol: 1, Pages: 276-281, ISSN: 2055-6640
The International AIDS Society (IAS) convened the Towards an HIV Cure Symposium on 18-19 July 2015 in Vancouver, Canada, bringing together researchers and community to discuss the most recent advances in our understanding of HIV latency, reservoirs and a summary of the current clinical approaches towards an HIV cure. The symposium objectives were to: (1) gather researchers and stakeholders to present, review, and discuss the latest research towards an HIV cure; (2) promote cross-disciplinary global interactions between basic, clinical and social scientists; and (3) provide a platform for sharing information among scientists, clinicians, funders, media and civil society. The symposium examined basic molecular science and animal model data, and emerging and ongoing clinical trial results to prioritise strategies and determine the viral and immune responses that could lead to HIV remission without antiretroviral therapy. This report summarises some of the major findings discussed during the symposium.
Thornhill J, Sivaramakrishnan A, Orkin C, 2015, Pneumococcal vaccination in people living with HIV, VACCINE, Vol: 33, Pages: 3159-3160, ISSN: 0264-410X
Wallis E, Thornhill J, Saunders J, et al., 2015, Introducing opt-out HIV testing in an acute medical admissions unit: does it improve testing uptake in those with lobar pneumonia?, SEXUALLY TRANSMITTED INFECTIONS, Vol: 91, Pages: 153-153, ISSN: 1368-4973
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