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Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy.

  • Author(s): von Stockenstrom, Susanne
  • Odevall, Lina
  • Lee, Eunok
  • Sinclair, Elizabeth
  • Bacchetti, Peter
  • Killian, Maudi
  • Epling, Lorrie
  • Shao, Wei
  • Hoh, Rebecca
  • Ho, Terence
  • Faria, Nuno R
  • Lemey, Philippe
  • Albert, Jan
  • Hunt, Peter
  • Loeb, Lisa
  • Pilcher, Christopher
  • Poole, Lauren
  • Hatano, Hiroyu
  • Somsouk, Ma
  • Douek, Daniel
  • Boritz, Eli
  • Deeks, Steven G
  • Hecht, Frederick M
  • Palmer, Sarah
  • et al.
Abstract

The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART).Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4(+) T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologic suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7-9 months.DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens.Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.

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