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

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Presentation on theme: "Contribution of naïve CD4+ T cells to the intact HIV reservoir"— Presentation transcript:

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

3 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

4 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

5 Pinzone et al. Nat Comm 2019

6 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

7 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

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

9 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

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

11 Tracking the clones

12 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.

13 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 R UM1, BELIEVE R CIP 2014.IT.05.SFOP.014/3/10.5/9.2.02/0006

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