Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells
Open Access
- 19 June 2017
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 127 (7), 2689-2696
- https://doi.org/10.1172/jci93289
Abstract
HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells.Keywords
This publication has 36 references indexed in Scilit:
- Bottlenecks in HIV-1 transmission: insights from the study of founder virusesNature Reviews Microbiology, 2015
- Th9 Cells: A Novel CD4 T-cell Subset in the Immune War against CancerCancer Research, 2015
- Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 CureCell, 2013
- Essentials of Th17 cell commitment and plasticityBlood, 2013
- Host Factor Transcriptional Regulation Contributes to Preferential Expression of HIV Type 1 in IL-4–Producing CD4 T CellsPublished by The American Association of Immunologists ,2012
- Opposing Signals from the Bcl6 Transcription Factor and the Interleukin-2 Receptor Generate T Helper 1 Central and Effector Memory CellsImmunity, 2011
- Homeostatic Proliferation Fails to Efficiently Reactivate HIV-1 Latently Infected Central Memory CD4+ T CellsPLoS Pathogens, 2011
- HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferationNature Medicine, 2009
- Rapid Reversion of Sequence Polymorphisms Dominates Early Human Immunodeficiency Virus Type 1 EvolutionJournal of Virology, 2007
- Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapyNature Medicine, 1999