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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, S
  • Odevall, L
  • Lee, E
  • Sinclair, E
  • Bacchetti, P
  • Killian, M
  • Epling, L
  • Shao, W
  • Hoh, R
  • Ho, T
  • Faria, NR
  • Lemey, P
  • Albert, J
  • Hunt, P
  • Loeb, L
  • Pilcher, C
  • Poole, L
  • Hatano, H
  • Somsouk, M
  • Douek, D
  • Boritz, E
  • Deeks, SG
  • Hecht, FM
  • Palmer, S
  • et al.
Abstract

© 2015 The Author. Background. 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). Methods. 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. Results. 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. Conclusions. 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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