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Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T-Cells are Highly Permissive to HIV-1 Infection

Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T-Cells are Highly Permissive to HIV-1 Infection. Patricia Monteiro, PhD Laboratory of Dr Petronela Ancuta Université de Montréal CHUM-Research Center, Saint-Luc Hospital, Montréal, Quebec, Canada XVIII International AIDS Conference

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Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T-Cells are Highly Permissive to HIV-1 Infection

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  1. Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T-Cells are Highly Permissive to HIV-1 Infection Patricia Monteiro, PhD Laboratory of Dr Petronela Ancuta Université de Montréal CHUM-Research Center, Saint-Luc Hospital, Montréal, Quebec, Canada XVIII International AIDS Conference Vienne, July 22, 2010

  2. Helper T-Cell Lineage SpecificationA New Understanding of CD4+ T-Cell Functional Heterogeneity Zhou L et al., Immunity, 2009

  3. Chemokine Receptors are Markers for CD4+ T-Cells with Distinct Lineage Commitment and Antigenic Specificity • CXCR3 regulates cell migration into inflamed tissues including the gut • CCR4 regulates cell migration into skin tissues • CCR6 mediates cell homing into the GALT  The permissiveness to HIV infection of these four memory CD4+ T-cell subsets remains unknown Acosta-Rodriguez et al., Nat. Immunol., 2007

  4. CD4+CD45RA- CCR4+ CXCR3+ Th17 Th1Th17 CCR6 CCR6 CCR4 Th2 Th1 CD4 CD4 CXCR3 p=0.015 p=0.0001 p=0.0001 p=0.015 p=0.01 Mann-Whitney test CCR4, CXCR3 and CCR6 Identify CD4+ T-Cells Subsets Expressing Cytokines and Transcription Factors Specific for Th17, Th2, Th1Th17, and Th1 Lineages Gosselin/Monteiro et al. J. Immunol. 2010

  5. P<0.0001 P<0.0001 P<0.0001 Th17 Th2 Th1Th17 Th1 Th17 Th2 Th1Th17 Th1 Mann-Whitney test Expression of the HIV Coreceptors CCR5 and CXCR4 on CD4+ T-Cells Expressing CCR4, CXCR3 and/or CCR6 Gosselin/Monteiro et al. J. Immunol. 2010

  6. Th17 Th17 Th2 Th2 Th1Th17 Th1Th17 Th1 Th1 Th17 Th2 Th1Th17 Th1 Th17 Th2 Th1Th17 Th1 CCR4+CCR6+ (Th17) et CXCR3+CCR6+ (Th1Th17) T-Cells are Highly Permissive to R5 and X4 HIV Replication Gosselin/Monteiro et al. J. Immunol. 2010

  7. P<0.0001 P=0.017 P=0.03 P<0.0001 P=0.04 P=0.028 Altered Heterogeneity of CD4+ T-Cells in HIV-Infected Patients Despite CD4 Count Normalization under ART Th17 Th1Th17 Th1 Th17 Th1Th17 Th1 Gosselin/Monteiro et al. J. Immunol. 2010

  8. P=0.03 P<0.0001 Mann-Whitney test Preferential Permissiveness to HIV-DNA Integration and Depletion of Memory CCR6+ T-Cells in HIV-Infected Patients Gosselin/Monteiro et al. J. Immunol. 2010

  9. p=0.0007 p=0.0052 p=0.0021 Th2 Th1 Th17 Th1Th17 Mann-Whitney test Expression of the Gut-Homing Integrin 7 on CD4+ T-Cell Subsets Expressing CCR4, CXCR3 and/or CCR6 Gosselin/Monteiro et al. J. Immunol. 2010

  10. CXCR4 CXCR4 CXCR4 CCR5 CXCR4 CCR5 CXCR4 CCR5 beta7 beta7 Infiltration of CCR6+ Th17 and Th1Th17 cells into sites of HIV replication in vivo (e.g., gut, vaginal mucosa, lymph nodes, and brain) Conclusions and Significance X4 HIV R5 HIV X4 HIV R5 HIV

  11. Acknowledgements Ancuta Lab – CHUM-Research Center INSERM U743 Annie Gosselin, PhD Vanessa Sue Wacleche, MSc Sekaly Lab – CHUM-Research Center INSERM U743, VGTI Nicolas Chomont, PhD Mohamed El-Far, PhD Flow Cytometry Core Facility – CHUM-Research Center Sylvain Gimmig Laurence Lejeune Primo infection cohort - McGill University Jean-Pierre Routy, MD Mohamed-Rachid Boulassel, PhD FRSQ-AIDS Infectious Diseases Network Anne Vassal Mario Legault HIV-infected and uninfected subjects for their gift of leukapheresis and essential contribution to this work

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