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1. Sickle Cell Trait and Kidney Disease in People of African Ancestry With HIV

Author

Rachel K.Y. Hung, Elizabeth Binns-Roemer, John W. Booth, Rachel Hilton, Julie Fox, Fiona Burns, Mark Harber, Andrew Ustianowski, Lisa Hamzah, James E. Burns, Amanda Clarke, David A. Price, Stephen Kegg, Denis Onyango, Beatriz Santana-Suarez, Lucy Campbell, Kate Bramham, Claire C. Sharpe, Caroline A. Sabin, Cheryl A. Winkler, Frank A. Post, John Booth, Anele Waters, James Hand, Chris Clarke, Sarah Murphy, Maurice Murphy, Marion Campbell, Celia Richardson, Alyson Knott, Gemma Weir, Rebecca Cleig, Helena Soviarova, Lisa Barbour, Tanya Adams, Vicky Kennard, Vittorio Trevitt, Rachael Jones, Jeremy Levy, Alexandra Schoolmeester, Serah Duro, May Rabuya, Deborah Jordan, Teresa Solano, Hiromi Uzu, Karen Williams, Julianne Lwanga, Linda Ekaette Reid-Amoruso, Hannah Gamlen, Robert J. Stocker, Fiona Ryan, Karina Mahiouz, Tess Cheetham, Claire Williams, Achyuta Nori, Caroline Thomas, Sivaraj Venkateshwaran, Jessica Doctor, Andrea Berlanga, Frank Post, Leigh McQueen, Priya Bhagwandin, Bee Barbini, Emily Wandolo, Tim Appleby, Lois Driver, Sophy Parr, Hongbo Deng, Julie Barber, Andrew Crowe, Chris Taylor, Mary Poulton, Vida Boateng, Marie-Pierre Klein, Caitlin O’Brien, Samuel Ohene-Adomako, Christian Buckingham, Daniel Trotman, Killian Quinn, Kate Flanagan, Verity Sullivan, Holly Middleditch, Itty Samuel, Elizabeth Hamlyn, Candice McDonald, Ana Canoso, Emeka Agbasi, Maria Liskova, Sarah Barber, Amanda Samarawickrama, Zoe Ottaway, Claire Norcross, Amelia Oliveira, Jane Minton, Gary Lamont, Ruby Cross, Gaushiya Saiyad, Shadia Ahmed, Rebecca Ashworth, Nicola Window, J. Murira, Khine Phyu, Gabriella Lindergard, Jonathan Shaw, Sarah Holland, Claire Fox, Jan Flaherty, Margaret-Anne Bevan, Valerie George, David Chadwick, Marie Branch, Pauline Lambert, Adele Craggs, Sarah Pett, Hinal Lukha, Nina Vora, Marzia Fiorino, Maria Muller Nunez, Deirdre Sally, Erica Pool, Rebecca Matthews, David Ashley Price, Tara Stothard, Bijal Patel, Ian McVittie, Ciara Kennedy, Uli Shwab, Brendan Payne, Sarah Duncan, Jill Dixon, Mathias Schmid, Adam Evans, Christopher Duncan, Ewan Hunter, Yusri Taha, Natasha Astill, Cheryl Winkler, Victor David, Jonathan Ainsworth, Rachel Vincent, Chloe Saad, Sarah Skinner, Hocine Azzoug, Judith Russell, Tarik Moussaoui, Emily Mabonga, Donna Ward, J. Francoise, W. Larbi, Sue Mitchell, A. Manning, V. Russell, Nnenna Ngwu, Jonathan Edwards, Nargis Hemat, Tom Fernandez, Filippo Ferro, Jorge Ferreira, Alice Nightingale, Tasha Oakes-Monger, Darwin Matila, Pedro Nogueira, Victoria Mutagwanya, Catherine Cosgrove, Catherine Emily Isitt, Helen Webb, Joyce Popoola, Kate Korley, Mark Mencias, Patricia Ribeiro, Rajeshwar Ramkhelawn, Sandra Oliva Lara, Sara Sajijad, Alan Winston, Amber Shaw, Claire Petersen, Kyle Ring, Melanie Rosenvinge, Thembi Moyo, Faith Odong, Katherine Gantert, Tina Ibe, Caroline Sabin, and Teresa Hill

Subjects
Africa, APOL1, HIV, kidney, SCT, sickle cell trait, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: Sickle cell trait (SCT) has been associated with chronic kidney disease (CKD) in African Americans, although evidence for its impact in Africans and people with HIV is currently lacking. We conducted a cross-sectional study investigating the association between SCT and kidney disease in people of African ancestry with HIV in the UK. Methods: The primary outcome was estimated glomerular filtration rate (eGFR) 50 mg/mmol), and albuminuria (albumin-to-creatinine ratio >3 mg/mmol). Multivariable logistic regression was used to estimate the associations between SCT and kidney disease outcomes. Results: A total of 2895 participants (mean age 48.1 [SD 10.3], 57.2% female) were included, of whom 335 (11.6%) had SCT and 352 (12.2%) had eGFR

Published
2022
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2. Genetic Variants of APOL1 Are Major Determinants of Kidney Failure in People of African Ancestry With HIV

Author

Rachel K.Y. Hung, Elizabeth Binns-Roemer, John W. Booth, Rachel Hilton, Mark Harber, Beatriz Santana-Suarez, Lucy Campbell, Julie Fox, Andrew Ustianowski, Catherine Cosgrove, James E. Burns, Amanda Clarke, David A. Price, David Chadwick, Denis Onyango, Lisa Hamzah, Kate Bramham, Caroline A. Sabin, Cheryl A. Winkler, Frank A. Post, John Booth, Anele Waters, James Hand, Chris Clarke, Sarah Murphy, Maurice Murphy, Marion Campbell, Celia Richardson, Alyson Knott, Gemma Weir, Rebecca Cleig, Helena Soviarova, Lisa Barbour, Tanya Adams, Vicky Kennard, Vittorio Trevitt, Rachael Jones, Jeremy Levy, Alexandra Schoolmeester, Serah Duro, May Rabuya, Deborah Jordan, Teresa Solano, Hiromi Uzu, Karen Williams, Julianne Lwanga, Linda Ekaette Reid-Amoruso, Hannah Gamlen, Robert J. Stocker, Fiona Ryan, Karina Mahiouz, Tess Cheetham, Claire Williams, Achyuta Nori, Caroline Thomas, Sivaraj Venkateshwaran, Jessica Doctor, Andrea Berlanga, Frank Post, Leigh McQueen, Priya Bhagwandin, Bee Barbini, Emily Wandolo, Tim Appleby, Lois Driver, Sophy Parr, Hongbo Deng, Julie Barber, Andrew Crowe, Chris Taylor, Mary Poulton, Vida Boateng, Marie-Pierre Klein, Caitlin O'Brien, Samuel Ohene-Adomako, Christian Buckingham, Daniel Trotman, Killian Quinn, Kate Flanagan, Verity Sullivan, Holly Middleditch, Itty Samuel, Elizabeth Hamlyn, Candice McDonald, Ana Canoso, Emeka Agbasi, Maria Liskova, Sarah Barber, Amanda Samarawickrama, Zoe Ottaway, Claire Norcross, Amelia Oliveira, Jane Minton, Gary Lamont, Ruby Cross, Gaushiya Saiyad, Shadia Ahmed, Rebecca Ashworth, Nicola Window, J. Murira, Khine Phyu, Gabriella Lindergard, Jonathan Shaw, Sarah Holland, Claire Fox, Jan Flaherty, Margaret-Anne Bevan, Valerie George, Marie Branch, Pauline Lambert, Adele Craggs, Sarah Pett, Hinal Lukha, Nina Vora, Marzia Fiorino, Maria Muller Nunez, Deirdre Sally, Erica Pool, Rebecca Matthews, David Ashley Price, Tara Stothard, Bijal Patel, Ian McVittie, Ciara Kennedy, Uli Shwab, Brendan Payne, Sarah Duncan, Jill Dixon, Mathias Schmid, Adam Evans, Christopher Duncan, Ewan Hunter, Yusri Taha, Natasha Astill, Cheryl Winkler, Victor David, Jonathan Ainsworth, Rachel Vincent, Stephen Kegg, Chloe Saad, Sarah Skinner, Hocine Azzoug, Judith Russell, Tarik Moussaoui, Emily Mabonga, Donna Ward, J. Francoise, W. Larbi, Sue Mitchell, A. Manning, V. Russell, Fiona Burns, Nnenna Ngwu, Jonathan Edwards, Nargis Hemat, Tom Fernandez, Filippo Ferro, Jorge Ferreira, Alice Nightingale, Tasha Oakes-Monger, Darwin Matila, Pedro Nogueira, Victoria Mutagwanya, Catherine Emily Isitt, Helen Webb, Joyce Popoola, Kate Korley, Mark Mencias, Patricia Ribeiro, Rajeshwar Ramkhelawn, Sandra Oliva Lara, Sara Sajijad, Alan Winston, Amber Shaw, Claire Petersen, Kyle Ring, Melanie Rosenvinge, Thembi Moyo, Faith Odong, Katherine Gantert, Tina Ibe, Caroline Sabin, and Teresa Hill

Subjects
kidney, Nephrology, Africa, HIV, diaspora, APOL1, HIVAN
Abstract

Introduction: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse. Methods: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of 2, chronic dialysis, or having received a kidney transplant). The secondary outcomes included renal impairment (eGFR 2), albuminuria (albumin-to-creatinine ratio [ACR] >30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes. Results: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22–17.99), renal impairment (OR 5.50, 95% CI 3.81–7.95), albuminuria (OR 3.34, 95% CI 2.00–5.56), and HIVAN (OR 30.16, 95% CI 12.48–72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes. Conclusion: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort.

Published
2022
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3. 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

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