title: The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time.
abstract: 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 naïve 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.
authors.affiliation: Department of Diagnostics and Vaccinology, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Josefsson
authors.forename: Susanne
authors.initials: S
authors.lastname: von Stockenstrom
authors.forename: Nuno R
authors.initials: NR
authors.lastname: Faria
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.forename: Peter
authors.initials: P
authors.lastname: Bacchetti
authors.forename: Maudi
authors.initials: M
authors.lastname: Killian
authors.forename: Lorrie
authors.initials: L
authors.lastname: Epling
authors.forename: Alice
authors.initials: A
authors.lastname: Tan
authors.forename: Terence
authors.initials: T
authors.lastname: Ho
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
authors.forename: Wei
authors.initials: W
authors.lastname: Shao
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.forename: Ma
authors.initials: M
authors.lastname: Somsouk
authors.forename: Will
authors.initials: W
authors.lastname: Wylie
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Lisa
authors.initials: L
authors.lastname: Loeb
authors.forename: Jeff
authors.initials: J
authors.lastname: Custer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.forename: Lauren
authors.initials: L
authors.lastname: Poole
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Frederick
authors.initials: F
authors.lastname: Hecht
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
mesh_terms: D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002353:Carrier State / Q000821:virology*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D009154:Mutation; D010802:Phylogeny; D013997:Time Factors
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral