60 results found
Paparini S, Whitacre R, Smuk M, et al., 2022, Public understanding and awareness of and response to monkeypox virus outbreak: A cross-sectional survey of the most affected communities in the United Kingdom during the 2022 public health emergency, HIV MEDICINE, ISSN: 1464-2662
Reuschl A-K, Mesner D, Shivkumar M, et al., 2022, HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells, CELL REPORTS, Vol: 39, ISSN: 2211-1247
Marques-Gomes J, Salt MJ, Pereira-Neto R, et al., 2021, Development of the HIV360 international core set of outcome measures for adults living with HIV: A consensus process, HIV MEDICINE, Vol: 23, Pages: 639-649, ISSN: 1464-2662
Reeves I, Cromarty B, Deayton J, et al., 2021, British HIV Association guidelines for the management of HIV-2 2021, HIV MEDICINE, Vol: 22, Pages: 1-29, ISSN: 1464-2662
Lee MJ, Snell LB, Douthwaite ST, et al., 2021, Clinical outcomes of patients with and without HIV hospitalized with COVID-19 in England during the early stages of the pandemic: a matched retrospective multi-centre analysis (RECEDE-C19 study), HIV Medicine, Vol: 23, Pages: 121-133, ISSN: 1464-2662
BackgroundThe contribution of HIV to COVID-19 outcomes in hospitalized inpatients remains unclear. We conducted a multi-centre, retrospective matched cohort study of SARS-CoV-2 PCR-positive hospital inpatients analysed by HIV status.MethodsHIV-negative patients were matched to people living with HIV (PLWH) admitted from 1 February 2020 to 31 May 2020 up to a 3:1 ratio by the following: hospital site, SARS-CoV-2 test date ± 7 days, age ± 5 years, gender, and index of multiple deprivation decile ± 1. The primary objective was clinical improvement (two-point improvement or better on a seven-point ordinal scale) or hospital discharge by day 28, whichever was earlier.ResultsA total of 68 PLWH and 181 HIV-negative comparators were included. In unadjusted analyses, PLWH had a reduced hazard of achieving clinical improvement or discharge [adjusted hazard ratio (aHR) = 0.57, 95% confidence interval (CI): 0.39–0.85, p = 0.005], but this association was ameliorated (aHR = 0.70, 95% CI: 0.43–1.17, p = 0.18) after additional adjustment for ethnicity, frailty, baseline hypoxaemia, duration of symptoms prior to baseline, body mass index (BMI) categories and comorbidities. Baseline frailty (aHR = 0.79, 95% CI: 0.65–0.95, p = 0.011), malignancy (aHR = 0.37, 95% CI 0.17, 0.82, p = 0.014) remained associated with poorer outcomes. The PLWH were more likely to be of black, Asian and minority ethnic background (75.0% vs 48.6%, p = 0.0002), higher median clinical frailty score [3 × interquartile range (IQR): 2–5 vs, 2 × IQR: 1–4, p = 0.0069), and to have a non-significantly higher proportion of active malignancy (14.4% vs 9.9%, p = 0.29).ConclusionsAdjusting for confounding comorbidities and demographics in a matched cohort ameliorated differences in outcomes of PLWH hospitalized with COVID-19, highlighting the importance of an appropriate comparison group when assessing outcomes of PLWH hospitalized with COVID-19.
Martin GE, Sen DR, Pace M, et al., 2021, Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
Burns JE, Stohr W, Kinloch-De Loes S, et al., 2021, Tolerability of four-drug antiretroviral combination therapy in primary HIV-1 infection, HIV MEDICINE, Vol: 22, Pages: 770-774, ISSN: 1464-2662
Thornhill J, Orkin C, 2021, Long-acting injectable HIV therapies: the next frontier: Republication, CURRENT OPINION IN HIV AND AIDS, Vol: 16, Pages: 98-105, ISSN: 1746-630X
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
Reuschl A-K, Shivkumar M, Mesner D, et al., 2021, HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells
<jats:p>Human immunodeficiency virus type 1 (HIV-1) replicates in CD4+ T cells leading to profound T cell loss, immunological dysfunction and AIDS. Determining how HIV-1 shapes the immunological niche in which it resides to create a permissive environment is central to informing efforts to limit pathogenesis, disturb viral reservoirs and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate CD4+ T cells <jats:italic>in vitro</jats:italic> in order to make them permissive to infection. This dramatically alters T cell biology, obscuring native virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient and productive infection of resting CD4+ T cells without the need for prior activation. Infection is preferential for resting memory T cells, is observed with both CXCR4-tropic virus and CCR5-tropic transmitter-founder viruses and results in virus production and onward spreading infection. Strikingly, we find that HIV-1 infection of resting memory CD4+ T cells primes for induction of a tissue-resident memory (T<jats:sub>RM</jats:sub>)-like phenotype evidenced by upregulation of T<jats:sub>RM</jats:sub> markers CD69/CXCR6 alongside co-expression of CD49a, PD-1, CD101 as well as transcription factor Blimp-1. Furthermore, we reveal that HIV-1 initiates a transcriptional program that overlaps with the core T<jats:sub>RM</jats:sub> transcriptional signature. This reprograming depends on the HIV-1 accessory protein Vpr. We propose that HIV-1 infection drives a CD4+ T<jats:sub>RM</jats:sub>-phenotype potentially sequestering infected cells within tissues to support viral replication and persistence.</jats:p>
Lee M, Smith CJ, Douthwaite S, et al., 2021, Clinical Outcomes of Patients With and Without HIV Hospitalised with COVID-19 in England During the Early Stages of the Pandemic: A Matched Retrospective Multicentre Analysis (RECEDE-C19 Study), SSRN Electronic Journal
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
Martin GE, Pace M, Shearer F, et al., 2019, HIV reservoir size is determined prior to ART initiation and linked to CD8 T cell activation and memory expansion
<jats:title>Abstract</jats:title><jats:p>Initiation of antiretroviral therapy (ART) in early compared with chronic HIV infection is associated with a smaller HIV reservoir. This longitudinal analysis of 63 individuals who commenced ART during primary HIV infection (PHI) investigates which pre-and post-therapy factors associate most closely with reservoir size (HIV DNA) following treatment initiation during PHI. The best predictor of reservoir size at one-year was pre-ART HIV DNA which was in turn significantly associated with CD8 memory differentiation (effector memory, naïve and T-bet<jats:sup>neg</jats:sup>Eomes<jats:sup>neg</jats:sup>subsets), CD8 T cell activation (CD38 expression) and PD-1 and Tim-3 expression on memory CD4 T cells. No associations were found for any immunological variables following one-year of ART. HIV reservoir size is determined around the time of ART initiation in individuals treated during PHI. CD8 T cell activation and memory expansion are linked to HIV reservoir size, suggesting the importance of the initial host-viral interplay in eventual reservoir size.</jats:p>
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, 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
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
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.
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