Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 51, Pages E4987-E4996Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1308313110
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Funding
- amfAR Research Consortium on HIV Eradication (ARCHE)
- Foundation for AIDS Research [amfAR 107857-48-RGRL]
- Delaney AIDS Research Enterprise [U19 AI096109]
- Swedish International Development Agency [SWE-2009-046]
- Swedish Research Council [K2011-56X-21749-01-6]
- National Institutes of Health (NIH) [AI071713, K24AI069994, K23 CA157929]
- UCSF-Gladstone Institute of Virology and Immunology Center for AIDS Research [P30AI027763, P30 MH59037]
- NIH/National Center for Research Resources UCSF Clinical and Translational Science Institute [UL1RR024131]
- European Union Seventh Framework Programme [FP7/2007-2013, 278433-PREDEMICS]
- European Research Council [260864]
- Erik and Edith Fernstrom Foundation for Medical Research
- Fundacao para a Ciencia e Tecnologia [SFRH/BD/64530/2009]
- Karolinska Institutet alumni funds
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The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naive and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4(+) T cells [CD45RO(+)/CD27((+/-))]. The HIV-1 infection frequency of CD4(+) T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4-12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4-12 y of suppressive therapy. We also identified a clearly replication incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.
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