Doherty Institute - Research Publications

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Author: Cameron, Paul × Author: Rhodes, Ajantha × End date: 2022 × Start date: 2020 ×

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    Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency
    Rasmussen, TA ; Zerbato, JM ; Rhodes, A ; Tumpach, C ; Dantanarayana, A ; McMahon, JH ; Lau, JSY ; Chang, JJ ; Gubser, C ; Brown, W ; Hoh, R ; Krone, M ; Pascoe, R ; Chiu, CY ; Bramhall, M ; Lee, HJ ; Haque, A ; Fromentin, R ; Chomont, N ; Milush, J ; Van der Sluis, RM ; Palmer, S ; Deeks, SG ; Cameron, PU ; Evans, V ; Lewin, SR (CELL PRESS, 2022-10-18)
    Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress CD4+ T cell activation and may promote latent HIV infection. By performing leukapheresis (n = 21) and lymph node biopsies (n = 8) in people with HIV on antiretroviral therapy (ART) and sorting memory CD4+ T cells into subsets based on PD1/CTLA4 expression, we investigate the role of PD1 and CTLA 4 in HIV persistence. We show that double-positive (PD1+CTLA4+) cells in blood contain more HIV DNA compared with double-negative (PD1-CTLA4-) cells but still have a lower proportion of cells producing multiply spliced HIV RNA after stimulation as well as reduced upregulation of T cell activation and proliferation markers. Transcriptomics analyses identify differential expression of key genes regulating T cell activation and proliferation with MAF, KLRB1, and TIGIT being upregulated in double-positive compared with double-negative cells, whereas FOS is downregulated. We conclude that, in addition to being enriched for HIV DNA, double-positive cells are characterized by negative signaling and a reduced capacity to respond to stimulation, favoring HIV latency.
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    Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy
    Anderson, JL ; Khoury, G ; Fromentin, R ; Solomon, A ; Chomont, N ; Sinclair, E ; Milush, JM ; Hartogensis, W ; Bacchetti, P ; Roche, M ; Tumpach, C ; Gartner, M ; Pitman, MC ; Epling, CL ; Hoh, R ; Hecht, FM ; Somsouk, M ; Cameron, PU ; Deeks, SG ; Lewin, SR (OXFORD UNIV PRESS INC, 2020-03-01)
    BACKGROUND: Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy. METHODS: Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry. RESULTS: Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines. CONCLUSIONS: HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.