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Single-Cell Analysis Shows Molecular Signatures of HIV Latency In CROI 2020 PP E-01 Mechanisms of Latency 306 7-11 March 2020 Contact Single-Cell Analysis Shows Molecular Signatures of HIV Latency in Primary Cell Models Name: Sushama Telwatte Address: 4150 Clement St San Francisco, CA 94121 1,2 3 4 5 1,2 6 6 5 3 Email: Sushama Telwatte , Mauricio Montano , Rachel S. Resop , Emilie Battivelli , Sara Morón-López , Douglas Arneson , Atul Butte , Eric Verdin , Warner C. Greene , [email protected] Alberto Bosque4, Joseph K. Wong1,2, Steven A. Yukl1,2 1. San Francisco VA Medical Center (SFVAMC), San Francisco, CA, USA 2. University of California, San Francisco (UCSF), San Francisco, CA, USA 3. Gladstone Institutes, San Francisco, CA, USA 4. George Washington University, Washington, DC, USA 5. The Buck Institute for Research on Aging, Novato, CA, USA 6. Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA Introduction Results • Primary cell models have greatly advanced our understanding of HIV latency. HIV expression drives the differences between populations across donors in the all of the primary cell model tested However, it is unclear which mechanisms underlie latency in these primary cell models. Dataset Group1 Group2 Differentially expressed genes (FDR p<0.05) Dataset Group1 Group2 Differentially expressed genes (FDR p<0.05) WT Virus HIV+ HIV- (exposed but UI) Long LTR, Gag, Gag (IPDA), Pol, env (IPDA), Nef, PolyA Resting Cell (blood CD4) Latent HIV+ HIV- (exposed but UI) Gag, env (IPDA), PolyA Resting Cell Model (Blood CD4) HIV+ Uninfected (HIV-unexposed) Long LTR, Gag, Gag (IPDA), Pol, env (IPDA), Nef, PolyA Latent HIV+ UI (unexposed/uninfected) Long LTR, Gag, Gag (IPDA), Pol, env (IPDA), PolyA Hypothesis: Molecular signatures can distinguish uninfected, latently- Dual Productive Latent Gag, Pol, env (IPDA), PolyA, Tat-Rev CDK13 is differentially-expressed between latently-infected, HIV-exposed but uninfected, and HIV- and productively-infected populations in these models Reporter Productive Uninfected Long LTR, Gag, Gag (IPDA), Pol, env (IPDA), PolyA, Tat-Rev Resting Cell (tonsil CD4) Latent (mCh-) UI (unexposed/uninfected) Long LTR, Gag, Gag (IPDA), Pol, env (IPDA), unexposed cells Latent Uninfected Long LTR, Gag, Gag (IPDA), Pol, env (IPDA), PolyA B Methods A Donor 11 Latent (HIV+) Donor 13 Latent (HIV+) • We assessed 4 primary cell models [blood CD4T cells: models from labs of Alberto Donor 11 HIV- (HIV-exposed) Donor 13 HIV- (HIV-exposed) Bosque1 (WT Virus Model), Eric Verdin2 (Dual Reporter Virus Model), and Warner Wild Type Virus Model Donor 11 UI (HIV-unexposed) Greene3,4 (Resting Cell Model); tissue (tonsillar) CD4+ T cells: model from Warner Upregulation of BCL6 and HLA-DR and of STAT1 distinguish latent HIV+ cells from Donor 13 UI (HIV-unexposed) Greene]. Single cells from each model (2 donors) were FACS-sorted into 96-well downregulation plates and multiplex RT-qPCR (Biomark HD) was used to quantify 88 human RNAs uninfected populations previously implicated in HIV infection/latency and 8 HIV targets (5'LTR, Gag, Pol, 5 Nef, MS Tat-Rev, U3-PolyA, and the IPDA assays for Env and Gag). We compared sampleID 30 sampleID MAIN FINDINGS HIV-unexposed, HIV-exposed but uninfected, and latently- +/- productively-infected A B BD77HIV+Donor 77 Latent (HIV+) Long LTR 25 *No Tat-Rev populations from each model to identify genes with ≥2-fold difference in median BD79HIV+Donor 79 Latent (HIV+) expression BD77HIVDonor 77 HIV− - (HIV-exposed) expression levels and P<0.05 or FDR-corrected P<0.05. Gag 20 ●Donor 11 HIV+●Donor 11 HIV−●Donor 11 UI detected BD79HIVDonor 79 HIV− - (HIV-exposed) ●Donor 13 HIV+●Donor 13 HIV−●Donor 13 UI Gag (IPDA) BD77UIDonor 77 UI (HIV-unexposed) C 15 WT Virus Model: All Genes No HIV Genes BD79UIDonor 79 UI (HIV-unexposed) ● Primary Cell Models ● ● Pol 2 ●● ● ● ● ● 10 ● ●● ● ● ● D ● ● ● ● ● • ● ● ● ● • Each model differed in the virus employed: BCL-6 and HLA-DR are ● 1 ● ● ● ● ● ● Env (IPDA) ●● ● ● 5 ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● PolyA sampleID upregulated and STAT1 is 0 ● ● ● ● ● ●●● Nef ● ● ● ● ● PolyA 0.6 GD11HIV+ 0 ● ● ● ● ● ● ● ● sampleID APOBEC3G PTB/PTBP1 IFI16 STAT1 SF2/ASF (SRSF1) GAPDH IRF9 G9a/EHMT2 OX40/TNFRSF4 NFKB1 PBAF/SMARCA4 BCL11B/CTIP2 PAPOLA POLR2A CDK9 beta7 integrin/ITGB7 KAT2B/PCAF BCL6 NELFA/WHS2 PRDM1/Blimp CD4 TCRA ELL SF3B2 BCL2 HLA CASP3 PAF TGFB1 FAS STING/TMEM173 SLFN11 FoxP3 TBX21/t TRIM5 CD28 CD3 delta CD44 C RIG CTLA4 GATA3 HTATSF1 MATR3 PPIA SAMHD1 CD69 NFATC1 p53 CDK11a CCR5 CREBBP/CBP PRMT6 PSIP1 MDA5/IFIH1 BST2/Tetherin IFNA1 NFKBIA CCNL2/cyclin L2 CXCR4 CCR7 CEBPB TCF7 CDK7 CDK13 RPL13a CD25/IL2RA LCK HDAC5 Sp1 EP300 EZH2 CCNT1 YY1 ● ● ● ● ● ● − GD13HIV+ ● ● ● ● ● ● ● ● ● GAS/MB21D1 0.4 − − UMAP_2 ● Wild Type Virus ● − ● I/DDX58 DR alpha ● ● ● 1 −1 ● ● ● ● ● ● 0.2 WT HIV-NL4.3 PolyA ● ● ● ● ● − downregulated in latent HIV+ ● ● bet ● ●● ●● 0 model ● ● ● ● Competent ● − −2 1 −0.2 Tat−Rev ● ● −0.4 cells vs. uninfected cells. ● −2 −1 0 1 2 −1 0 1 2 UMAP_1 C D Fig. 4(A) Schematic of Resting Cell model (blood and tonsillar CD4 T cells). Resting Cell ●Donor 77 HIV+●Donor 77 HIV−●Donor 77 UI ●Donor 79 HIV+●Donor 79 HIV−●Donor 79 UI Single-cell data generated (blood CD4 T cells) are represented by (B) heat HIVmCherry-LUC All Genes No HIV Genes 0.3 sampleID model 4 Dual Reporter Virus Model: map for HIV transcript expression (C) UMAP projections with/without HIV ● PolyA Table 4. Differentially expressed genes between Resting Cell Model (blood CD4 T) populations ●● ●● ● BD77HIV+,BD79HIV+ ● ●●● Competent* ● ●●●● ● ● 0.2 ● ●● ● ● ● ●● ● targets, and (D) correlation matrix showing degree of correlation between ●● ● ●● ● ● Ave. Log ●● ●● ●● ● ●● ● ● 2 ● ●● ● ● ● ● ● ● ● ●● Group1 Group2 gene p_val N1 N2 FDR ● ● ●●● ●● ● ● ● ● ●● ● Tat−Rev • ● ● ● ● ●● ●● ● CDK7, CEBPB and Cyclin L2 expression of each cellular gene (columns) and HIV RNA-specific PolyA ● ● ● ● ●● ● ● ● ● 0.1 Fold Change ● ● ●● ● ● ● ●● ● ●● ●● ● ● ● ●●● ● ● ●● sampleID NFKB1 CDKN1A ELL HTATSF1 CCR7 CDK13 BST2/Tetherin CTLA4 HDAC5 PAF APOBEC3G ATF BCL6 IFI16 CREBBP/CBP RIG beta7 integrin/ITGB7 G9a/EHMT2 PRDM1/Blimp TRIM5 NFATC1 TNFRSF8 CD38 CDK9 GATA3 FAS Sp1 PTB/PTBP1 HLA LCK TCF7 CCNL2/cyclin L2 CXCR4 STAT1 SUV39H1 EP300 OX40/TNFRSF4 MDA5/IFIH1 p53 CCNT1 TBX21/t YY1 ZNF431 BCL11B/CTIP2 CD69 STING/TMEM173 KAT2B/PCAF CD44 EZH2 CEBPB MATR3 C CD4 GAPDH CASP3 CDK7 EGR1 POLR2A TCRA CD28 BCL2 SAMHD1 FoxP3 TRBP/TARBP RPL13a SF2/ASF (SRSF1) PRMT6 IFNA1 CDK11a PPIA CCR5 CD3 delta Ki67/MKI67 SLFN11 IRF9 NELFA/WHS2 NFKBIA CD25/IL2RA PAPOLA PSIP1 TGFB1 PBAF/SMARCA4 SF3B2 Greene’s model ●● ●● ● ● ● ● ● ●● ●● ●●● ● ● ●● ● ● ● − ● ● ● ●● ● ● ● ● ● ● Latent (HIV+) HIV- (HIV-exposed) CDK13 0.001 -1.266 29 6 0.022 (rows). PolyA is grouped by donor (Donor 11 and 13). Color scale (right) ● GAS/MB21D1 0 ●● ● ●● ● ●● ●●● ●● ● ●● ● ●●● ● ● − 0 ● ● ● − ● ● ● − ● ● ●● ● ● − Dual Reporter ● ● ● ● ● I/DDX58 ● ● ● ● DR alpha ● ● ● 3 ● ● ● ● 1 distinguish latent HIV+ cells HIV- (HIV-exposed) UI (HIV-unexposed) CDK13 7.3E-05 1.795 6 30 0.005 indicates Spearman r values. UMAP_2 ● ●● ● ● ● ● ● ●●● ● ● ● ● ● ● − ● ● ● ● ●● ● HIV-GKO ● ● ● ● bet −0.1 −2 ●● ● ● ● ● ● ● ● ●● ● ● ● ● Virus model ● ● ●● ● ● ● ●●●● ● ● ● ● ●● ●● ● ●● ● ●● ●● ●● ●● ● ● ●● − vs. uninfected cells ● ●● ● −0.2 Incompetent 1 ● ● ● ●●● −4 ●● ● −2 −1 0 1 2 −2 −1 0 1 2 −0.3 Resting Cell Model (Tonsil CD4) Assay Panel UMAP_1 Table 1. Cellular and HIV targets in single-cell multiplex qPCR panel Upregulation of transcriptional factors, immune checkpoint markers, T cell phenotypic/function Fig. 2 (A) Schematic of Wild Type (WT) Virus model. Sorted single cells from the WT Virus model populations were analyzed for HIV expression by a qPCR-based pre-screen Resting Cell Model: followed by a multiplex qPCR for 96 HIV and cellular targets (Biomark HD platform)[Table 1]. Single-cell data generated are represented by (B) heat map to demonstrate cell- associated genes in productive tonsillar CD4 T cells compared to latent (mCherry-) and HIV-unexposed to-cell variation in levels of each HIV target (rows), where each vertical line represents a single cell, (C) UMAP projections with/without HIV targets, and (D) correlation matrix Blood CD4 T cells: cells●GTD1SmCh+●GTD1SmCh−●GTD1mCh−●GTD1UI●GTD1mCh+ showing degree of correlation between expression of each cellular gene (columns) and HIV RNA-specific target (rows) (n=2 donors). Color scale (right) indicates Spearman r ●GTD3SmCh+●GTD3SmCh−●GTD3mCh−●GTD3UI values. • CDK13 is downregulated in 35 Table 2. Differentially expressed genes between WT Virus primary cell model populations sampleID sampleID All Genes No HIV Genes Donor 1 Productive (mCh+)[Stim.] GTD1SmCh+ ●● ● 30 Donor 1 Productive (mCh+)[Stim.] ● ●●● ● Long LTR 2 ●● ● ●●● ● Donor 3 Productive (mCh+)[Stim.] Ave. Log Fold GTD3SmCh+ ● ● ● ●● ● latent cells compared to A Donor 3 Productive (mCh+)[Stim.] B ●● ● ● Group1 Group2 gene p_val N1 N2 FDR ● 25 ●● ● ● ●● Donor 1 Productive (mCh+) Change GTD1mCh+Donor 1 Productive (mCh+) ● ● ● ● Gag 1 ● ● ● ● ● ●● ● ● ● ●● ● ● GTD1SmCh− ● ●● ● ● ● ● ●● Donor 1 Latent (mCh-) [Stim.] Latent (HIV+) HIV- (HIV-exposed) BCL6 0.001 1.598 102 15 0.016 20 Donor 1 Latent (mCh-) [Stim.] ● ● ● ● ● ● ● ● ● ● ● Gag (IPDA) GTD3SmCh− ● ● ● ● ● ● ● ●● uninfected populations Donor 3 Latent (mCh-) [Stim.] ● ● ● ● ● Donor 3 Latent (mCh-) [Stim.] 0 ● ● ●● ● Latent (HIV+) UI (HIV unexposed) HLA-DR alpha 0.004 1.319 102 37 0.036 ●● ●● ● ● ●● 15 GTD1mCh− ●● ● ● ● ●●● ● ● ● Donor 1 Latent (mCh-) UMAP_2 ● ● ● ● ● ● ● ● ● ● Donor 1 Latent (mCh-) Latent (HIV+) UI (HIV unexposed) STAT1 2.19E-04
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