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Blood CXCR3+ CD4 T Cells Are Enriched in Inducible Replication Competent HIV

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Blood CXCR3+ CD4 T Cells Are Enriched in Inducible Replication Competent HIV Blood CXCR3+ CD4 T cells are enriched in Inducible Replication Competent HIV 1Riddhima Banga, 1Francesco Procopio, 2Matthias Cavassini 1,3Giuseppe Pantaleo and 1Matthieu Perreau 1Service of Immunology and Allergy Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland, 2Infectious Diseases, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, 3Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland Abstract Results Background. We recently demonstrated that Lymph node (LN) PD-1+/T follicular Figure 1: Gating strategy for sorting blood memory CD4 T cells based on chemokine receptor expression Figure 3: Percentage of cells expressing HIV receptors CCR5 and CXCR4 and restriction factor SAMHD1 helper (Tfh) cells from anti-retroviral therapy (ART) treated HIV-infected HIV receptors Restriction factor individuals were enriched in cells containing replication competent virus. However, Gated on CD3+CD4+CD45RA- the distribution of cells containing inducible replication competent virus has been Selection of blood #10 #20 Integrated DNA CCR5 CXCR4 SAMHD1 #12 #26 CD4 T-cell populations only partially elucidated in blood memory CD4 T-cell populations including the Tfh #14 #35 CCR5 5 10 30 100 cell counterpart circulating in blood (cTfh). #16 #43 60 5 TFH- like TH1TFH- like 5 TH2- like TH17 - like 10 #18 #45 populations 10 populations * /million) 4 Methods. We have investigated the distribution of 1) total HIV-1 infected cells by CXCR5 + CXCR3 + CCR4 + CCR4 + 10 cell populations cell 4 CXCR5 + 4 CCR6 + 10 cells 20 80 10 expressing 40 Alu PCR and 2) cells containing replication competent HIV using virus outgrowth containing 3 expressing SAMHD1 expressing SAMHD1 10 cell expressing CXCR4 assay (VOA) within blood memory CD4 T-cell populations defined by chemokine T 3 cells 10 3 cells 10 2 cells cells 10 of + - - + receptor expression i.e CXCR3 CXCR5 (Th1), CXCR3 CXCR5 (cTfh), 10 20 60 102 + + + + 0 10 1 CXCR3 CXCR5 (Th1 cTfh), CCR4+CCR6- (Th2), and CCR4 CCR6 (Th17) 0 TH1- like CXCR3 + CCR4 cells in ART treated (1.5-8 years) aviremic (<20 HIV RNA copies/ml) individuals CXCR5 0 Frequency Frequency 10 0 0 40 2 3 4 5 2 3 4 5 (N=11). 0 10 10 10 10 0 10 10 10 10 ( Integrated HIV DNA CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CCR6 CXCR5 CCR6 CXCR5 CCR6 CXCR5 CXCR3 CCR6 CCR6 CXCR5 among sorted blood among among sorted blood CD4 T Percentage of Percentage of CD4 T among among sorted blood CD4 T Results. No significant differences in the frequency of integrated HIV DNA in the Percentage of CD4 T different memory CD4 T-cell populations were found (P>0.05). However, blood Percentage of CD4 T Th1 cells were significantly enriched in cells containing replication competent virus Figure 2: Frequencies of cells containing replication competent virus by viral outgrowth assay (VOA) Figure 4: Percentage of cells expressing differentiation markers : CCR7 and CD27 as compared to any other blood CD4 T-cell population (P<0.05). The mean frequency of Th1 cells containing inducible replication competent virus was about 9 Patients #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 TN CM TM EM cells per million as assessed by RNA-Unit Per Million. Blood Th1 cells were also Allogeneic CD8-depleted PBMCs * N.S* the largest contributor (42%) to the total pool of blood HIV-infected cells containing from HIV negative subject Limiting 100 dilution replication competent virus in the cohort. Interestingly, the fraction of HIV provirus format cells 80 induced by VOA was higher in Th1 cells as compared to any other blood CD4 T-cell 60 subpopulations, suggesting that Th1 cells contained either more intact or more Results 1. Levels of HIV RNA 40 inducible provirus. Of note, blood CD4 T-cell populations were not significantly 2. Frequencies of replication competent virus 3. Proportion of provirus induced 20 different in terms of 1) level of activation as assessed by HLA-DR or Ki-67 4.Contribution to the total pool of cells containing replication competent virus in blood Percentage of CD4 T expression, 2) CCR5 and CXCR4 HIV co-receptor expression and 3) SAMHD1 0 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 HIV restriction factor expression (P>0.05). However, both Th1 and cTfh cells were expressing differentiation markers CCR6 CXCR5 CCR6 CXCR5 CCR6 CXCR5 CCR6 CXCR5 significantly enriched in PD-1 expressing cells as compared to Th2 and Th17 (46% and 42%, respectively) (P<0.05), but only the levels of HIV RNA of Th1 VOA Figure 5: Percentage of cells expressing activation markers HLA-DR and Ki-67 Levels HIV-1 RNA Frequency: RUPM culture supernatants directly correlated with the frequency of PD-1 expression on DR 5 67 Th1 cells (P<0.05). 10 20 - * #10 #20 HLA-DR Ki Ki-67 Conclusions. Taken together, these results indicate that blood Th1 cells represent #12 #26 4 * 10 30 10 #14 #43 the major blood compartment containing inducible replication competent virus in 15 populations #16 #45 populations 8 3 cell containing containing treated aviremic HIV-infected individuals. 10 #18 #47 cell expressing populations (copies/ml) 20 #35 expressing HLA- 10 cells 6 cells cell 2 of 10 cells Study group at enrollment 4 10 1 5 10 2 Frequency Frequency 0 10 0 0 0 Duration CD4 Cell Viral Load replication competent virus [RUPM] Time on supernatant in VOA RNA Levels of HIV-1 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 Subject of HIV Count at at HAART sorted blood CD4 T CCR6 CXCR5 CCR6 CXCR5 Percentage of Percentage of CD4 T CCR6 CXCR5 CCR6 CXCR5 among sorted blood CD4 T among among sorted blood CD4 T Percentage of Percentage of CD4 T Age Sex HAART of ID infection enrollment Enrollment regimen (years) (years) (cells/ul) (copies/ml) Figure 6: Levels of HIV RNA of CXCR3+ VOA culture supernatants correlate with frequency of PD-1 + expression on CXCR3 cells #10 49 M 9.1 543 <20 8.8 EFV; 3TC Inducible provirus cell Contribution -1 -1 0.4 50 PD PD-1 cells 42% 80 10 5 #12 30 F 8.4 453 <20 2.9 3TC/r; ABC 40 N.S populations populations 0.3 * * populations 4 CXCR3 10 cell 60 r = 0.7 38 10.1 3.5 30 cell #14 M 1691 <20 EFV; TDF; FTC expressing populations p = 0.01 0.2 10 3 cell sorted blood CD4 T - 20 cells 40 #16 50 M 25.9 487 <20 14.2 ETR; DRV/r; RAL 10 2 each 0.1 CD4 T 10 20 + 10 1 #18 46 M 2.6 376 <20 2.5 FTC; TDF; EFV [RUPM] / INT DNA*100 0 0.0 0 0 10 Percentage of Percentage of inducible provirus population population to the total pool of 0 20 40 60 80 #20 25 F 25.3 480 <20 14.1 ETR; DRV/r; RAL CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 CXCR3 CCR4 CCR4 CXCR5 CXCR3 of CXCR3 within sorted blood CD4 T CCR6 CXCR5 CCR6 CXCR5 Contribution of CCR6 CXCR5 Levels of HIV-1 RNA in VOA supernatant in VOA RNA Levels of HIV-1 Percentage of CD4 T cells expressing PD-1 Percentage of Percentage of CD4 T among among sorted blood CD4 T + containg containg replication competent virus in blood (%) among CXCR3 CD4 T-cell populations #26 51 M 9.6 666 <20 9.6 3TC, ABC, DTG #35 26 M 2.1 1219 <20 1.8 FTC, TDF, EVG Conclusions #43 37 M 2.8 605 <20 2.8 3TC, ABC, DTG In the present study, we demonstrated that #45 41 M 8.0 442 <20 7.9 FTC, TDF, ETR 1. Blood CXCR3+ CD4 T cell subset is enriched in cells containing inducible replication competent virus; 2. Blood CXCR3+ CD4 T cells contribute the most (42%) to the total pool of cells containing replication competent virus in blood; #47 34 F 0.2 972 <20 0.1 3TC, ABC, DTG 3. The levels of HIV RNA of blood CXCR3+ CD4 T cells VOA culture supernatants directly correlated with the frequency of PD-1 expression on Th1 cells .
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