Marie-Angélique De Scheerder1,2, Clarissa Van Hecke1, Henrik Zetterberg3,4,5,6, Dietmar Fuchs7, Nele De Langhe1, Sofie Rutsaert1, Bram Vrancken8, Wim Trypsteen1, Ytse Noppe1, Bea Van Der Gucht2, Jolanda Pelgrom2, Filip Van Wanzeele2, Sarah Palmer9, Philippe Lemey8, Magnus Gisslén10,11, Linos Vandekerckhove1,2. 1. HIV Cure Research Center, Department of Internal Medicine and Paediatrics, Faculty of Medicine and Health Sciences, Ghent University and Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium. 2. Department of General Internal Medicine and Infectious Diseases, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium. 3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. 4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 5. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK. 6. UK Dementia Research Institute at UCL, London, UK. 7. Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innrain 52, Christoph-Probst-Platz, 6020 Innsbruck, Austria. 8. KU Leuven Department of Microbiology and Immunology, Rega Institute, Laboratory of Evolutionary and Computational Virology, Leuven, Belgium. 9. Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, New South Wales 2145, Australia. 10. Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Wallinsgatan 6, Mölndal, Sweden. 11. Department of Infectious Diseases, Sahlgrenska University Hospital, 11 Region Västra Götaland, Gothenburg, Sweden.
Abstract
BACKGROUND: Validated biomarkers to evaluate HIV-1 cure strategies are currently lacking, therefore requiring analytical treatment interruption (ATI) in study participants. Little is known about the safety of ATI and its long-term impact on patient health. OBJECTIVES: ATI safety was assessed and potential biomarkers predicting viral rebound were evaluated. METHODS: PBMCs, plasma and CSF were collected from 11 HIV-1-positive individuals at four different timepoints during ATI (NCT02641756). Total and integrated HIV-1 DNA, cell-associated (CA) HIV-1 RNA transcripts and restriction factor (RF) expression were measured by PCR-based assays. Markers of neuroinflammation and neuronal injury [neurofilament light chain (NFL) and YKL-40 protein] were measured in CSF. Additionally, neopterin, tryptophan and kynurenine were measured, both in plasma and CSF, as markers of immune activation. RESULTS: Total HIV-1 DNA, integrated HIV-1 DNA and CA viral RNA transcripts did not differ pre- and post-ATI. Similarly, no significant NFL or YKL-40 increases in CSF were observed between baseline and viral rebound. Furthermore, markers of immune activation did not increase during ATI. Interestingly, the RFs SLFN11 and APOBEC3G increased after ATI before viral rebound. Similarly, Tat-Rev transcripts were increased preceding viral rebound after interruption. CONCLUSIONS: ATI did not increase viral reservoir size and it did not reveal signs of increased neuronal injury or inflammation, suggesting that these well-monitored ATIs are safe. Elevation of Tat-Rev transcription and induced expression of the RFs SLFN11 and APOBEC3G after ATI, prior to viral rebound, indicates that these factors could be used as potential biomarkers predicting viral rebound.
BACKGROUND: Validated biomarkers to evaluate HIV-1 cure strategies are currently lacking, therefore requiring analytical treatment interruption (ATI) in study participants. Little is known about the safety of ATI and its long-term impact on patient health. OBJECTIVES: ATI safety was assessed and potential biomarkers predicting viral rebound were evaluated. METHODS: PBMCs, plasma and CSF were collected from 11 HIV-1-positive individuals at four different timepoints during ATI (NCT02641756). Total and integrated HIV-1 DNA, cell-associated (CA) HIV-1 RNA transcripts and restriction factor (RF) expression were measured by PCR-based assays. Markers of neuroinflammation and neuronal injury [neurofilament light chain (NFL) and YKL-40 protein] were measured in CSF. Additionally, neopterin, tryptophan and kynurenine were measured, both in plasma and CSF, as markers of immune activation. RESULTS: Total HIV-1 DNA, integrated HIV-1 DNA and CA viral RNA transcripts did not differ pre- and post-ATI. Similarly, no significant NFL or YKL-40 increases in CSF were observed between baseline and viral rebound. Furthermore, markers of immune activation did not increase during ATI. Interestingly, the RFs SLFN11 and APOBEC3G increased after ATI before viral rebound. Similarly, Tat-Rev transcripts were increased preceding viral rebound after interruption. CONCLUSIONS: ATI did not increase viral reservoir size and it did not reveal signs of increased neuronal injury or inflammation, suggesting that these well-monitored ATIs are safe. Elevation of Tat-Rev transcription and induced expression of the RFs SLFN11 and APOBEC3G after ATI, prior to viral rebound, indicates that these factors could be used as potential biomarkers predicting viral rebound.
Authors: Marie-Angélique De Scheerder; Bram Vrancken; Simon Dellicour; Timothy Schlub; Eunok Lee; Wei Shao; Sofie Rutsaert; Chris Verhofstede; Tessa Kerre; Thomas Malfait; Dimitri Hemelsoet; Marc Coppens; Annemieke Dhondt; Danny De Looze; Frank Vermassen; Philippe Lemey; Sarah Palmer; Linos Vandekerckhove Journal: Cell Host Microbe Date: 2019-08-27 Impact factor: 21.023
Authors: Steven A Yukl; Philipp Kaiser; Peggy Kim; Sushama Telwatte; Sunil K Joshi; Mai Vu; Harry Lampiris; Joseph K Wong Journal: Sci Transl Med Date: 2018-02-28 Impact factor: 17.956
Authors: Aylin Yilmaz; Kaj Blennow; Lars Hagberg; Staffan Nilsson; Richard W Price; Judith Schouten; Serena Spudich; Jonathan Underwood; Henrik Zetterberg; Magnus Gisslén Journal: Expert Rev Mol Diagn Date: 2017-06-14 Impact factor: 5.225
Authors: Katherine E Clarridge; Jana Blazkova; Kevin Einkauf; Mary Petrone; Eric W Refsland; J Shawn Justement; Victoria Shi; Erin D Huiting; Catherine A Seamon; Guinevere Q Lee; Xu G Yu; Susan Moir; Michael C Sneller; Mathias Lichterfeld; Tae-Wook Chun Journal: PLoS Pathog Date: 2018-01-11 Impact factor: 6.823
Authors: Mohamed Abdel-Mohsen; Rui André Saraiva Raposo; Xutao Deng; Manqing Li; Teri Liegler; Elizabeth Sinclair; Mohamed S Salama; Hussam El-Din A Ghanem; Rebecca Hoh; Joseph K Wong; Michael David; Douglas F Nixon; Steven G Deeks; Satish K Pillai Journal: Retrovirology Date: 2013-10-16 Impact factor: 4.602
Authors: Lorenzo Gaetani; Kina Höglund; Lucilla Parnetti; Fani Pujol-Calderon; Bruno Becker; Paolo Eusebi; Paola Sarchielli; Paolo Calabresi; Massimiliano Di Filippo; Henrik Zetterberg; Kaj Blennow Journal: Alzheimers Res Ther Date: 2018-01-23 Impact factor: 6.982
Authors: Karen L Diepstra; Liz Barr; David Palm; Evelyn Hogg; Katie R Mollan; Laney Henley; Angela M Stover; Jane M Simoni; Jeremy Sugarman; Brandon Brown; John A Sauceda; Steven Deeks; Lawrence Fox; Rajesh T Gandhi; Davey Smith; Jonathan Z Li; Karine Dubé Journal: AIDS Res Hum Retroviruses Date: 2021-02-16 Impact factor: 1.723
Authors: Rosa Bellmann-Weiler; Lukas Lanser; Francesco Burkert; Stefanie Seiwald; Gernot Fritsche; Sophie Wildner; Andrea Schroll; Sabine Koppelstätter; Katharina Kurz; Andrea Griesmacher; Günter Weiss Journal: Open Forum Infect Dis Date: 2020-11-03 Impact factor: 3.835
Authors: Marie-Angélique De Scheerder; Ward P H van Bilsen; Melissa Dullaers; Javier Martinez-Picado; Udi Davidovich; Linos Vandekerckhove Journal: J Virus Erad Date: 2021-01-23
Authors: Marion Pardons; Linos Vandekerckhove; Basiel Cole; Laurens Lambrechts; Pierre Gantner; Ytse Noppe; Noah Bonine; Wojciech Witkowski; Lennie Chen; Sarah Palmer; James I Mullins; Nicolas Chomont Journal: Nat Commun Date: 2021-06-17 Impact factor: 14.919