Contribution of naïve CD4+ T cells to the intact HIV reservoir

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Contribution of naïve CD4+ T cells to the intact HIV reservoir Emmanuele Venanzi Rullo, MD @lelevenanzi Share your thoughts on this presentation with #IAS2019

Maybe just one image to say quickly after ART dna undetect Maybe just one image to say quickly after ART dna undetect. But reservoir not cleared

Near full-length single genome proviral sequencing 5 DNA fragmentation/ligation of adapters at limiting dilution, library preparation 6 Sequence on Illumina MiniSeq 7 De novo Assembly 8 Determine Intact Sequences by presence of: psi packaging element complete ORFs critical splice sites 4 Screen for Positives and purify DNA Ho Cell 2013 Bruner Nat Med 2016 Imamichi PNAS 2016 Heiner Cell Reports 2017 Lee JCI 2017

Pinzone et al. Nat Comm 2019

Apheresis sample available Longitudinal study Subject Years off ART Nadir CD4 Viral peak Coreceptor Timepoints sampled 1 21 yrs 295 12,000 100% R5 2 and 9 yrs post ART 2 6 yrs 0 CD4+ 750,000 X4R5 Chronic patients Two ends of a spectrum (fast vs slow progressor, X4 vs R5, 0 vs 300 CD4+) Successfully treated Apheresis sample available Longitudinal study

Sorting strategy Tscm Tn Subset Purity % Tn 95.7 Tscm 66.9 Tcm 89.3 TEMRA (Tian Nat Com 2017) Tscm Tn Can contain Treg (Van den Broek Nat 2018) TD (Chomont Nat Com 2009) Subset Purity % Tn 95.7 Tscm 66.9 Tcm 89.3 Ttm 87 Tem 91.5 CD45dim 94

Naive Memory HIV copies/ million CD4+ cells Subj. 1 Subj. 2

Tn Tem 2y post art Subj. 1 9 yrs 2 yrs Subj. 2 9 yrs 0-10% clones 30% intact 7% intact 2% intact Tn 21% intact 0-10% clones 3% intact 1% intact 11% intact 18% intact 50-60% clones Tem

Number of intact proviruses/ million CD4+ cells 58.7% 38.5% 34.7% 58.3% 2 yrs 9 yrs 2 yrs 9 yrs

Tracking the clones

Take-home message TN have low integration level but higher % of intact proviruses vs memory T cells TN can be one of the major contributors to the reservoir They represent a new hurdle to the eradication because: Long lived More Transcriptionally silent (so less immune pressure) Can be activated and replenish the “memory reservoir” These cells should no longer be ignored.

Acknowledgements Lab members Marilia Pinzone LaMont Cannon Manuela Ceccarelli Sam Weissman Flow Core Paul Hallberg Jonni Moore Richard Schretzenmair Hank Pletcher Acknowledgements PIs: Una O’Doherty (University of Pennsylvania) Giuseppe Nunnari (University of Messina) Funding R01-120011 UM1, BELIEVE R21-143564 CIP 2014.IT.05.SFOP.014/3/10.5/9.2.02/0006