Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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ItemNo Preview AvailableShort-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study(ELSEVIER INC, 2015-12)BACKGROUND: In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study. METHODS: In this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371. FINDINGS: Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1·7 (95% CI 1·3-2·2; p<0·0001) to the timepoint during disulfiram treatment and 2·1 (1·5-2·9; p<0·0001) to the timepoint after disulfiram in the 500 mg group; 1·9 (1·6-2·4; p<0·0001) and 2·5 (1·9-3·3; p<0·0001) in the 1000 mg group; and 1·6 (1·2-2·1; p=0·0026) and 2·1 (1·5-3·1; p=0·0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses. INTERPRETATION: Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV. FUNDING: The Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council.
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ItemThymic plasmacytoid dendritic cells are susceptible to productive HIV-1 infection and efficiently transfer R5 HIV-1 to thymocytes in vitro(BMC, 2011-06-03)BACKGROUND: HIV-1 infection of the thymus contributes to the defective regeneration and loss of CD4+ T cells in HIV-1-infected individuals. As thymic dendritic cells (DC) are permissive to infection by HIV-1, we examined the ability of thymic DC to enhance infection of thymocytes which may contribute to the overall depletion of CD4+ T cells. We compared productive infection in isolated human thymic and blood CD11c+ myeloid DC (mDC) and CD123+ plasmacytoid DC (pDC) using enhanced green fluorescent protein (EGFP) CCR5 (R5)-tropic NL(AD8) and CXCR4 (X4)-tropic NL4-3 HIV-1 reporter viruses. Transfer of productive HIV-1 infection from thymic mDC and pDC was determined by culturing these DC subsets either alone or with sorted thymocytes. RESULTS: Productive infection was observed in both thymic pDC and mDC following exposure to R5 HIV-1 and X4 HIV-1. Thymic pDC were more frequently productively infected by both R5 and X4 HIV-1 than thymic mDC (p = 0.03; n = 6). Thymic pDC efficiently transferred productive R5 HIV-1 infection to both CD3(hi) (p = 0.01; mean fold increase of 6.5; n = 6) and CD3(lo) thymocytes (mean fold increase of 1.6; n = 2). In comparison, transfer of productive infection by thymic mDC was not observed for either X4 or R5 HIV-1. CONCLUSIONS: The capacity of thymic pDC to efficiently transfer R5 HIV-1 to both mature and immature thymocytes that are otherwise refractory to R5 virus may represent a pathway to early infection and impaired production of thymocytes and CD4+ T cells in HIV-1-infected individuals.
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ItemNo Preview AvailableThe role of SNPs in the α-chain of the IL-7R gene in CD4+T-cell recovery in HIV-infected African patients receiving suppressive cART(NATURE PUBLISHING GROUP, 2012-01)We previously found an association between faster CD4+ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-α (IL-7Rα) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n=352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Rα single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n=57). Soluble (s)IL-7Rα levels were measured by ELISA. In UARTO, IL-7Rα haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P=0.020) and no association was found with LMM (P=0.958). The tagging-SNP for IL-7Rα haplotype-2 (rs6897932) was associated with decreased sIL-7Rα (P<0.001). The haplotypes for the IL-7Rα were significantly different in Africans and Caucasians. Using IL-7Rα genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P=0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P=0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Rα haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Rα SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.
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ItemNo Difference in the Rate of Change in Telomere Length or Telomerase Activity in HIV-Infected Patients after Three Years of Darunavir/Ritonavir with and without Nucleoside Analogues in the MONET Trial(PUBLIC LIBRARY SCIENCE, 2014-11-04)OBJECTIVE: To determine whether nucleos(t)ide reverse transcriptase inhibitors (NRTI) contribute to an accelerated loss in telomere length (TL) in HIV-infected patients on antiretroviral therapy (ART). DESIGN: Substudy of randomised controlled trial. METHODS: Patients with HIV RNA <50 copies/mL on combination ART (n = 256) were randomised to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 127) or with 2 NRTIs (n = 129) for up to 144 weeks. TL and telomerase activity was quantified on stored peripheral blood mononuclear cells (PBMC; n = 124) using quantitative real time PCR. RESULTS: Patients in the sub-study had a mean age of 44 years and had received NRTI for a mean of 6.4 years (range 1-20 years). As expected, older patients have significantly shorter TL (p = 0.006), while women had significantly longer TL (p = 0.026). There was no significant association between TL and either the duration of prior NRTI treatment (p = 0.894) or the use of a PI versus NNRTI (p = 0.107). There was no significant difference between patients who continued or ceased NRTI in the mean change/year of TL or telomerase (p = 0.580 and 0.280 respectively). CONCLUSION: Continuation versus cessation of NRTI treatment was not associated with an accelerated loss in TL or telomerase activity.
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ItemNo Preview AvailableLipopolysaccharide, Immune Activation, and Liver Abnormalities in HIV/Hepatitis B Virus (HBV)-Coinfected Individuals Receiving HBV-Active Combination Antiretroviral Therapy(OXFORD UNIV PRESS INC, 2014-09-01)We investigated the relationship between microbial translocation, immune activation, and liver disease in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection. Lipopolysaccharide (LPS), soluble CD14, CXCL10, and CCL-2 levels were elevated in patients with HIV/HBV coinfection. Levels of LPS, soluble CD14, and CCL-2 declined following receipt of HBV-active combination antiretroviral therapy (cART), but the CXCL10 level remained elevated. No markers were associated with liver disease severity on liver biopsy (n = 96), but CXCL10, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α, and interferon γ (IFN-γ) were all associated with elevated liver enzyme levels during receipt of HBV-active cART. Stimulation of hepatocyte cell lines in vitro with IFN-γ and LPS induced a profound synergistic increase in the production of CXCL10. LPS may contribute to liver disease via stimulating persistent production of CXCL10.
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ItemNo Preview AvailablePanobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial(ELSEVIER INC, 2014-10)BACKGROUND: Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. METHODS: In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. FINDINGS: We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased significantly at all timepoints when patients were taking panobinostat (p < 0·0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3·5-fold (range 2·1-14·4). Panobinostat induced plasma viraemia with an odds ratio of 10·5 (95% CI 2·2-50·3; p = 0·0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. INTERPRETATION: Panobinostat effectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to significantly affect the latent HIV reservoir. FUNDING: The Danish Council for Strategic Research and Aarhus University.
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ItemEffect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma(LIPPINCOTT WILLIAMS & WILKINS, 2015-02-20)
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ItemActivation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy(PUBLIC LIBRARY SCIENCE, 2014-11)UNLABELLED: Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT01365065.