Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8+ Tcell antiviral responses.

Hongbing Yang ,Christopher P Conlon ,Andrew Alexander Knox ,Zoe Cuthbertson ,Johnson Mak ,Margaret M Johnson ,Juan Tiraboschi ,Lucy Dorrell ,Isabel Jendrulek ,Angelica Corcuera ,Shaadi Shidfar ,Hiromi Uzu ,Jane Anderson ,Nadia Castrillo Martinez ,Patrick O’rourke ,Hinal Lukha ,Nnenna Ngwu ,Geraldine M Gillespie ,Alex F Markham ,Martin Fisher ,Taras Zarko Flynn ,Alison Crook ,Myra O Mcclure ,Margherita Bracchi ,Sabine Kinloch-De Loës ,Tristan Barber ,Katie Topping ,Yinka Sowunmi ,Tomáš Hanke ,Heather Lewis ,Mark R Wills ,Simon Collins ,Sarah Fidler ,Eric Sandström ,Nicola Robinson ,Maryam Khan ,Christine Weaver ,Rebecca Gleig ,Lervina Thomas ,Cherry I Kingsley ,Amanda Clarke ,Veronica Miller ,Mark Nelson ,John Frater ,Colin Fitzpatrick ,Wolfgang Stöhr ,Nicola Ternette ,Matthew Pace ,Hanna Box ,Fleur Hudson ,Timothy Ea Peto ,Alice M Nightingale ,Michelle Gabrielle ,Beatriz Mothe ,Serge Fedele ,Jakub Kopycinski ,S Kaye ,Abdel Babiker ,Andrew Lovell ,Mark Taylor ,Aminata Sy ,Sarah Pett ,Ming Liu ,Adam Gregory ,Patrick O Byrne ,Helen Brown ,Marzia Fiorino ,Julie M Fox ,Mala K Maini ,Dominic Hague ,Janet Darbyshire ,Maddalena Cerrone ,Peter Bourke ,Alexandra Schoolmeesters ,Kristin Kuldanek ,Anuska Llano ,Darren B Leneghan ,Christian Berthou ,Peter Sasieni ,Martin Jones ,Annette Von Delft ,Damian J Kelly ,Orla Thunder ,Mikaila Bandara ,John Thornhill ,Charlotte Russell ,Axel Fun ,I V D Weller ,Simon Merle ,Tanya Adams ,Christopher Higgs ,Gemma Wood ,Jane Rowlands ,Gaynor Lawrenson ,Tina Fernandez ,Samandhy Cedeño ,Mary Rauchenberger ,Fiounnuala Finnerty ,Vittorio Trevitt ,Natalia Olejniczak ,Andrew Lever ,Otto Erlwein ,Frank A Post ,Nneka Nwokolo ,Rachel C Bennett ,Julianne Lwanga ,Tammy Murray

doi:10.1016/j.celrep.2021.109103

Hongbing Yang , Christopher P Conlon + Show 105 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109103

Copy DOI

Journal: Cell reports	Publication Date: May 1, 2021
Citations: 4	License type: cc-by

Abstract

Persistence of HIV through integration into host DNA in CD4+ Tcells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8+ Tcells are triggered to kill infected CD4+ Tcells 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+ Tcell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4+ Tcells prior to virus production invitro. 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.

Highlights

Antiretroviral therapy (ART) effectively suppresses HIV replication, yet treatment is not curative once infection is established in the host
By interrogating the histocompatibility leukocyte antigen (HLA) class I-associated immunopeptidome for HIV epitopes presented in the intracellular eclipse phase of the viral life cycle, we identified an HLA-A*02:01-restricted Gag Spacer Peptide 2 (SP2, known as p1) epitope, FLGKIWPSH (FH9), that is preferentially presented in the eclipse phase
Kinetics of HIV Gag expression in primary CD4+ T cells during the intracellular eclipse phase We first established an in vitro infection model to show that activated bulk primary CD4+ T cells harboring HIV in the pre-integration phase after infection could be identified by detection of intracellular Gag prior to new virion production

Summary

Introduction

Antiretroviral therapy (ART) effectively suppresses HIV replication, yet treatment is not curative once infection is established in the host. The CD4+ T cell clones that harbor these inducible proviruses (typically 1 per million resting CD4+ T cells) are thought to persist as a result of homeostatic or antigen-driven proliferation (Chomont et al, 2009; Bui et al, 2017; Reeves et al, 2018). These rare cells present a major challenge for host immune control or viral eradication

Methods

Results

Discussion

Conclusion