What are HIV-specific CD8 T cells missing to

What are HIV-specific CD8 T cells missing to kill the enemy? Lydie Trautmann @TwitterHandle Share your thoughts on this presentation with #IAS2019 The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, or HJF. Disclosure The author has no conflict of interest to disclose The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, or HJF Viral control in SIV can be mediated by CD8 T cells CD8 T cell depletion leads to viral rebound, suggesting viral control mediated by CD8 T cells in: ART treated SIV-infected macaques Cartwright E, Immunity 2016 Macaques who received bNAbs early after SHIV infection and showed sustained control Nishimura Y, Nature 2017 3BNC117+10-1074 bNAbs at days 3, 10 and 17 control SHIV viremia Deplete CD8, NK, NKT, T

Deplete CD8 Loss of viremic control with CD8 depletion CD8 T cells are not enough to induce HIV control HIV-specific CD8 T cells control HIV replication only in elite controllers HIV-specific CD8 T cells are dysfunctional in chronic infection Post-treatment controllers do not show CD8-mediated control Therapeutic vaccines have not induced HIV remission so far Fellay J, Science 2007; Pereyra F, Science 2010 Day C, Nature 2006; Trautmann L, Nat Med 2006 Sez-Cirin A, PLoS Pathog 2013 Pollard RB, Lancet Infect Dis 2014 Sneller MC, Sci Transl Med 2017 CD8 T cells are not enough to induce HIV control even when the reservoir is small ART initiation in acute infection did not lead to HIV control after ART cessation Tue 23 July, HIV remission and control trials Sacdalan C

Plasma Viral load at ART reinitiation (copies/ml) Colby DJ, Nat Med 2018 r= -0.83, *p= 0.0154 105 104 103 0 Ki-67+CD8+ Viral rebound after ART interruption in RV254 participants who started ART in acute infection 10 20 30 T cells at viral rebound (%) HIV-specific CD8 T cells negatively correlated with plasma VL at ART reinitiation in people who

initiated ART in FI but not in other Fiebig RV254 participants Different features of immune responses for prevention and treatment For prevention, immune responses need to: Target multiple HIV clades For treatment, immune responses need to: T cell responses need to be: Target HIV variants in one individual Broad Be persistent over time after vaccination Be potent at ART interruption Potent and sensitive

Block one virus at site of entry in mucosa Block a swarm of virus at multiple sites in the body Numerous and fast Outline Are HIV-specific CD8 T cells missing breath? Do they have enough affinity to eliminate HIV-infected cells? Are they too exhausted even on ART? What are they missing when ART is initiated in acute infection? Where do we go from there? Breadth of HIV-specific CD8 T cells Few epitopes are required in SIV to induce control Mudd PA, Nature 2012 SG, Nature Large breadth developed after RhCMV vaccine that induces 60% protection Hansen 2011 and 2013 EL, J Immunol 2009;

HIV-specific CD8 T cells were detected in the blood in Fiebig II/III Turnbull Goonetilleke, JEM 2009 Limited number of epitopes recognized in AHI with increased breadth over time Radebe, JID 2011; Radebe, AIDS 2015 Limitations of these studies: Limited number of donors studied in Fiebig I/II Assays not very sensitive CD8 T cells at peak viremia in AHI have a reduced cytokine response after in vitro stimulation Trautmann, Blood 2012; Ndhlovu, Immunity 2015, Takata Sci Transl Med 2017 Breadth of HIV-specific CD8 T cells in acute infection Breadth of HIV-specific CD8 T cells in AHI and CHI FI Mean 3.8 FII 8.6 FIII 8.7 FIV/ CHI V 11.0 9.8

Min- 0-7.5 1.5-18 3-19.5 4-16.5 0-18 Max Estimate number of peptides recognized in a single person HIV protein coverage by HIVspecific CD8 T cells in AHI CD8+T cell responses 100 Frequency of responding participants in all stages (%) Frequency of HIV-specific CD8 T cells in AHI and CHI 80 60 40 20 0 Gag Pol Vif Vpu/VprRev/Tat Env Nef

HIV proteins Breadth of HIV-specific CD8 T cell responses in acute infection averages 10 epitopes and is identical to chronic infection starting in Fiebig II and cover all HIV proteins Subra C, unpublished RV254 participants Killing reactivated HIV-infected cells on ART HIV-specific CD8 T cells in AHI impact viral set point Streeck H, J Virol 2014; Ndhlovu et al, Immunity 2015 HIV-specific CD8 T cells impact HIV reservoir seeding after ART initiation Takata STM 2017 But HIV-infected cells might be different during productive infection and after reactivation from the latent reservoir pool Good target Productively infected CD4 T cell Difficult target Reactivated latently infected CD4 T cell Reactivated latently-infected cells may be resistant to HIV-specific CD8 T cell killing Huang SH, J Clin Invest 2018

Infected CD4 T cells in HIV infection harbor more defective viruses than in SIV infection Bender AM, Cell Host Microbe 2019 TCR affinity influences HIV reservoir cells killing JR, J Exp Med 2007; HIV-specific CD8 T cells with high affinity TCR better control viral replicationAlmeida Almeida JR, Blood 2009 Nef-specific Gag-specific Gag-specific CD8CD8dependent independent HIV-specific CD8 T cell clones with high affinity TCR (CD8-independent) have a better reservoir killing capacity Lima NS, submitted HIV-specific CD8 T cell numbers and function on ART ART reduces the frequencies of HIV-specific CD8 T cells Ogg GS, J Immunol. 1999; Cassaza JP, J Immunol. 2001 ART partially restores polyfunctionality, and normalizes activation, exhaustion markers and survival markers Rehr M, J Virol. 2008; Janbazian L, J Immunol. 2012; Vigano S, J Virol. 2015; Mahnke YD, Pathog Immun 2016 1500 1000 Fiebig I Fiebig II Fiebig III

Fiebig IV/V Chronic 500 C hr on ic I-V 0 Fi eb ig Wed 24 July, Pathogenesis: And the band plays on Takata H PD-1 expression (MFI) ART in acute infection limits PD-1 expression on HIV-specific CD8 T cells and preserves their proliferation capacity **** 2000

RV254 participants HIV-specific CD8 T cell numbers and function on ART Absolute cell number in peripheral blood Specific Killing (E/T=2) 60 *** Fiebig I Fiebig II Fiebig III Fiebig IV/V Chronic 40 20 C hr on ic Fi eb ig

I-V 0 HIV-specific CD8+ T cells (cells/ ml) Recalled HIV-specific CD8 T cells 101 **** ** Wed 24 July, Pathogenesis: And the band plays on Takata H Fiebig I Fiebig II Fiebig III Fiebig IV/V Chronic * 100 10-1 10-2

ig eb i F I g bi e Fi V II- ic on r h C HIV-specific CD8 T cells from people treated in acute infection have superior killing capacity but have lower cell number than that from treated in chronic infection RV254 participants Summary HIV-specific CD8 T cell features: Generated early in Fiebig I Have a breadth and coverage at peak viremia similar to chronic infection Impact viral set point and reduce reservoir seeding in acute infection HIV-specific CD8 T cell responses after ART:

Need to have high TCR affinity to eliminate reactivated HIV-infected cells Do not recover proliferation and cytotoxic potential if not treated in acute infection Contribute to lower viral load at rebound following ATI only if treated in Fiebig I Do not have sufficient numbers when ART initiated in acute infection Therapeutic vaccines: a high bar pDNA vaccine Vorinostat + ChAd63/MVA Viral outgrowth assay + T ART only ART + LRA + Vaccine ~ 100 therapeutic vaccines tested, the vast majority showing no effect Sneller, Sci Trans Med 2017; Fidler, AIDS2018 Where to we go from there? Lower reservoir Not strong enough

Not low enough Stronger immunity latent virus HIV reservoir 10 -100 times lower than in Fiebig I needed immunity Higher numbers? Higher breadth? Higher affinity? Location? Rapid HIV-specific CD8 T cell response needed Hill, PNAS 2014 and Plos Pathogens 2016; Henrich, 2017 IAS Migueles, Nature Immunol 2002; Walker-Sperling, JV 2015 Participants of RV254 and Remission trials U.S. MHRP Nelson Michael Sandhya Vasan Merlin Robb Robert Gramzinski Jintanat Ananworanich

Julie Ake Diane Bolton Morgane Rolland Sodsai Tovanabutra Rasmi Thomas Mark de Souza Linda Jagodzinski Shelly Krebs Trevor Crowell Suteera Pinyakorn Flow Core Industry Thai Gov Pharm Organization ViiV Healthcare Gilead Merck Monogram Acknowledgements Thai Red Cross Praphan Phanuphak Nipat Teeratakulpisarn Nittaya Phanuphak Eugene Kroon Donn Colby Nitiya Chomchey Carlo Sacdalan James Fletcher

Pornpen Tantivitayakul Phillip Chan Jintana Intasan Many more MHRP Cellular Montral U Immunology Section Nicolas Chomont Hiroshi Takata Louise Leyre Caroline Subra Remi Fromentin Julie Mitchell Noemia Lima Drexel U Faria Fatmi Elias Haddad Jueyon Kakazu Roshell Muir Shu-Wei Wu Kelsi Jameson Kenneth Dietze Yale Alexander Haregot Serena Spudich Nikiah Dawson UCSF Victor Valcour AFRIMS Robert O Connell Alexandra Schuetz

Siriwat Akapirak Denise Hsu Rapee Trichavaroj Bessara Nantapinit Pornsuk Visudhiphan COG Chulalongkorn U Supranee Buranapraditkun Cornell U Sunee Sirivichayakul Brad Jones Rungsun Rerknimitr Szu-Han Huang Sukalya Lerdlum Phandee Wattanaboonyongcharoen Sopark Manasnayakorn Funding from U.S. MHRP Program, R01AI108433, R01MH106466

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