HIV-1 persistence in CD4+ T cells with stem cell-like properties
Maria J Buzon, Hong Sun, Chun Li, Amy Shaw, Katherine Seiss, Zhengyu Ouyang, Enrique Martin-Gayo, Jin Leng, Timothy J Henrich, Jonathan Z Li, Florencia Pereyra, Ryan Zurakowski, Bruce D Walker, Eric S Rosenberg, Xu G Yu, Mathias Lichterfeld, Maria J Buzon, Hong Sun, Chun Li, Amy Shaw, Katherine Seiss, Zhengyu Ouyang, Enrique Martin-Gayo, Jin Leng, Timothy J Henrich, Jonathan Z Li, Florencia Pereyra, Ryan Zurakowski, Bruce D Walker, Eric S Rosenberg, Xu G Yu, Mathias Lichterfeld
Abstract
Cellular HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4(+) T memory stem cells (TSCM cells) harbor high per-cell levels of HIV-1 DNA and make increasing contributions to the total viral CD4(+) T cell reservoir over time. Moreover, we conducted phylogenetic studies that suggested long-term persistence of viral quasispecies in CD4(+) TSCM cells. Thus, HIV-1 may exploit the stem cell characteristics of cellular immune memory to promote long-term viral persistence.
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References
- Finzi D, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5:512–517.
- Chomont N, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893–900.
- Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–712.
- Lanzavecchia A, Sallusto F. Progressive differentiation and selection of the fittest in the immune response. Nat Rev Immunol. 2002;2:982–987.
- Fearon DT, Manders P, Wagner SD. Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science. 2001;293:248–250.
- Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med. 2005;11:1299–1305.
- Papatriantafyllou M. T cell memory: the stem of T cell memory. Nat Rev Immunol. 2011;11:716.
- Ahmed R, Bevan MJ, Reiner SL, Fearon DT. The precursors of memory: models and controversies. Nat Rev Immunol. 2009;9:662–668.
- Emerson SG. T memory stem cells: looking for stem cells in an immune haystack. Trans Am Clin Climatol Assoc. 2008;119:289–293. discussion 293–284.
- Gattinoni L, et al. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17:1290–1297.
- Cieri N, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013;121:573–584.
- Gattinoni L, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med. 2009;15:808–813.
- Lugli E, et al. Superior T memory stem cell persistence supports long-lived T cell memory. J Clin Invest. 2013
- Lugli E, et al. Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells. Nat Protoc. 2012;8:33–42.
- Walker BD, Yu XG. Unravelling the mechanisms of durable control of HIV-1. Nat Rev Immunol. 2013;13:487–498.
- Ho YC, et al. Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure. Cell. 2013;155:540–551.
- Takahashi-Yanaga F, Kahn M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res. 2010;16:3153–3162.
- Katlama C, et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013
- Liszewski MK, Yu JJ, O’Doherty U. Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods. 2009;47:254–260.
- Pasternak AO, et al. Highly sensitive methods based on seminested real-time reverse transcription-PCR for quantitation of human immunodeficiency virus type 1 unspliced and multiply spliced RNA and proviral DNA. J Clin Microbiol. 2008;46:2206–2211.
- Mbisa JL, Delviks-Frankenberry KA, Thomas JA, Gorelick RJ, Pathak VK. Real-time PCR analysis of HIV-1 replication post-entry events. Methods Mol Biol. 2009;485:55–72.
- Brussel A, Delelis O, Sonigo P. Alu-LTR real-time nested PCR assay for quantifying integrated HIV-1 DNA. Methods Mol Biol. 2005;304:139–154.
- Buzon MJ, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16:460–465.
- Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009;347:70–78.
- Sharkey M, et al. Episomal viral cDNAs identify a reservoir that fuels viral rebound after treatment interruption and that contributes to treatment failure. PLoS Pathog. 2011;7:e1001303.
- Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol. 2007;24:1596–1599.
- Herbeck JT, et al. Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes. J Virol. 2011;85:7523–7534.
- Jordan MR, et al. Comparison of standard PCR/cloning to single genome sequencing for analysis of HIV-1 populations. J Virol Methods. 2010;168:114–120.
- Josefsson L, et al. Hematopoietic precursor cells isolated from patients on long-term suppressive HIV therapy did not contain HIV-1 DNA. J Infect Dis. 2012;206:28–34.
Source: PubMed