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Start Over Author "Tina Fernandez" Topic 0302 clinical medicine
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1. Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8(+) T cell antiviral responses

Author

Hongbing Yang, Anuska Llano, Samandhy Cedeño, Annette von Delft, Angelica Corcuera, Geraldine M. Gillespie, Andrew Knox, Darren B. Leneghan, John Frater, Wolfgang Stöhr, Sarah Fidler, Beatriz Mothe, Johnson Mak, Christian Brander, Nicola Ternette, Lucy Dorrell, Eric Sandström, Janet Darbyshire, Frank Post, Christopher Conlon, Jane Anderson, Mala Maini, Timothy Peto, Peter Sasieni, Veronica Miller, Ian Weller, Abdel Babiker, Sarah Pett, Matthew Pace, Natalia Olejniczak, Helen Brown, Nicola Robinson, Jakub Kopycinski, Tomáš Hanke, Alison Crook, Steven Kaye, Myra McClure, Otto Erlwein, Andrew Lovell, Maryam Khan, Michelle Gabrielle, Rachel Bennett, Aminata Sy, Adam Gregory, Fleur Hudson, Charlotte Russell, Gemma Wood, Hanna Box, Cherry Kingsley, Katie Topping, Andrew Lever, Mark Wills, Axel Fun, Mikaila Bandara, Damian Kelly, Simon Collins, Alex Markham, Mary Rauchenberger, Yinka Sowunmi, Shaadi Shidfar, Dominic Hague, Mark Nelson, Maddalena Cerrone, Nadia Castrillo Martinez, Tristan Barber, Alexandra Schoolmeesters, Christine Weaver, Orla Thunder, Jane Rowlands, Christopher Higgs, Serge Fedele, Margherita Bracchi, Lervina Thomas, Peter Bourke, Nneka Nwokolo, Gaynor Lawrenson, Marzia Fiorino, Hinal Lukha, Sabine Kinloch-de Loes, Margaret Johnson, Alice Nightingale, Nnenna Ngwu, Patrick Byrne, Zoe Cuthbertson, Martin Jones, Tina Fernandez, Amanda Clarke, Martin Fisher, Rebecca Gleig, Vittorio Trevitt, Colin Fitzpatrick, Tanya Adams, Fiounnuala Finnerty, John Thornhill, Heather Lewis, Kristin Kuldanek, Julie Fox, Julianne Lwanga, Hiromi Uzu, Ming Lee, Simon Merle, Patrick O’Rourke, Isabel Jendrulek, Taras Zarko Flynn, Mark Taylor, Juan Manuel Tiraboschi, Tammy Murray, group, Research in Viral Eradication of Reservoirs (RIVER) trial study, Imperial College Healthcare NHS Trust- BRC Funding, and Medical Research Council (MRC)

Subjects
0301 basic medicine, immunopeptidome, DETERMINANTS, LYMPHOCYTES, 0601 Biochemistry and Cell Biology, Epitope, kinetics, 0302 clinical medicine, Cytotoxic T cell, CD8 T cells, mass spectrometry, Gag, cytotoxic T lymphocytes, HLA, POLYFUNCTIONALITY, INFECTED-CELLS, peptides, Life Sciences & Biomedicine, Antigen presentation, Human leukocyte antigen, PROVIRUSES, Biology, antigen presentation, REPLICATION CAPACITY, General Biochemistry, Genetics and Molecular Biology, Virus, 03 medical and health sciences, Immune system, CONTROLLERS, KINETICS, Science & Technology, RECOGNITION, HIV, Cell Biology, Virology, Histocompatibility, Research in Viral Eradication of Reservoirs (RIVER) trial study group, 030104 developmental biology, 1116 Medical Physiology, RESERVOIR, 030217 neurology & neurosurgery, CD8
Abstract

Persistence of HIV through integration into host DNA in CD4(+) T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8(+) T cells are triggered to kill infected CD4(+) T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial'' HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A*02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8(+) T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4(+) T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

Published
2021

2. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial

Author

Sarah Fidler, Wolfgang Stöhr, Matt Pace, Lucy Dorrell, Andrew Lever, Sarah Pett, Sabine Kinloch-de Loes, Julie Fox, Amanda Clarke, Mark Nelson, John Thornhill, Maryam Khan, Axel Fun, Mikaila Bandara, Damian Kelly, Jakub Kopycinski, Tomáš Hanke, Hongbing Yang, Rachel Bennett, Margaret Johnson, Bonnie Howell, Richard Barnard, Guoxin Wu, Steve Kaye, Mark Wills, Abdel Babiker, John Frater, Eric Sandström, Janet Darbyshire, Frank Post, Christopher Conlon, Jane Anderson, Mala Maini, Timothy Peto, Peter Sasieni, Veronica Miller, Ian Weller, Matthew Pace, Natalia Olejniczak, Helen Brown, Nicola Robinson, Alison Crook, Steven Kaye, Myra McClure, Otto Erlwein, Andrew Lovell, Michelle Gabrielle, Aminata Sy, Adam Gregory, Fleur Hudson, Charlotte Russell, Gemma Wood, Hanna Box, Cherry Kingsley, Katie Topping, Simon Collins, Alex Markham, Mary Rauchenberger, Yinka Sowunmi, Shaadi Shidfar, Dominic Hague, Maddalena Cerrone, Nadia Castrillo Martinez, Tristan Barber, Alexandra Schoolmeesters, Christine Weaver, Orla Thunder, Jane Rowlands, Christopher Higgs, Serge Fedele, Margherita Bracchi, Lervina Thomas, Peter Bourke, Nneka Nwokolo, Gaynor Lawrenson, Marzia Fiorino, Hinal Lukha, Alice Nightingale, Nnenna Ngwu, Patrick Byrne, Zoe Cuthbertson, Martin Jones, Tina Fernandez, Martin Fisher, Rebecca Gleig, Vittorio Trevitt, Colin Fitzpatrick, Tanya Adams, Fiounnuala Finnerty, Heather Lewis, Kristin Kuldanek, Julianne Lwanga, Hiromi Uzu, Ming Lee, Simon Merle, Patrick O'Rourke, Isabel Jendrulek, Taras ZarkoFlynn, Mark Taylor, Juan Manuel Tiraboschi, and Tammy Murray

Subjects
Adult, Male, medicine.medical_specialty, Disease reservoir, Transcription, Genetic, HIV Infections, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Adverse effect, Disease Reservoirs, AIDS Vaccines, Vorinostat, Intention-to-treat analysis, business.industry, General Medicine, Histone Deacetylase Inhibitors, Clinical trial, Regimen, Treatment Outcome, Anti-Retroviral Agents, DNA, Viral, business, Viral load
Abstract

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 regimens—have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18–60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI −0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.

Published
2020
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