title: Lack of concordance between residual viremia and viral variants driving de novo infection of CD4(+) T cells on ART.
abstract: In most patients, current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load. However, even after years of effective treatment, a significant proportion of patients show residual plasma viremia below the clinical detection limit. Although residual viremia might be associated with increased chronic immune activation and morbidity, its origin and its potential role in the replenishment of the viral reservoir during suppressive ART is not completely understood. We performed an in-depth genetic analysis of the total and episomal cell-associated viral DNA (vDNA) repertoire in purified CD4(+) T cell subsets of three HIV-infected individuals, and used phylogenetic analysis to explore its relationship with plasma viruses.
  
  
  
  The predominant proviral reservoir was established in naïve or memory (central and transitional) CD4(+) T cell subsets in patients harboring X4- or R5-tropic viruses, respectively. Regardless of the viral tropism, most plasma viruses detected under suppressive ART resembled the proviral reservoir identified in effector and transitional memory CD4(+) T-cell subsets in blood, suggesting that residual viremia originates from these cells in either blood or lymphoid tissue. Most importantly, sequences in episomal vDNA in CD4(+) T-cells were not well represented in residual viremia.
  
  
  
  Viral tropism determines the differential distribution of viral reservoir among CD4(+) T-cell subsets. In spite of viral tropism, the effector and transitional memory CD4(+) T-cells subsets are the main source of residual viremia during suppressive ART, even though their contribution to the total proviral pool is small. However, the lack of concordance between residual viremia and viral variants driving de novo infection of CD4(+) T cells on ART may reflect the predominance of defective plasma HIV RNA genomes. These findings highlight the need for monitoring the multiple viral RNA/DNA persistence markers, based on their differential contribution to viral persistence.
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Puertas
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Universitat de Vic - Universitat Central de Catalunya (UVic-UCC), Vic, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Noguera-Julian
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Département de Microbiologie, Infectiologie et Immunologie, Centre de Recherche du CHUM et Université de Montréal, Montreal, Canada.
authors.forename: Marta
authors.initials: M
authors.lastname: Massanella
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Stockholm, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Pou
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Buzon
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|"Lluita Contra la Sida" Foundation, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Universitat de Vic - Universitat Central de Catalunya (UVic-UCC), Vic, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|"Lluita Contra la Sida" Foundation, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Universitat de Vic - Universitat Central de Catalunya (UVic-UCC), Vic, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Universitat de Vic - Universitat Central de Catalunya (UVic-UCC), Vic, Spain.
authors.forename: Julià
authors.initials: J
authors.lastname: Blanco
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. jmpicado@irsicaixa.es.|Universitat de Vic - Universitat Central de Catalunya (UVic-UCC), Vic, Spain. jmpicado@irsicaixa.es.|Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. jmpicado@irsicaixa.es.
authors.forename: Javier
authors.identifier: 0000-0002-4916-2129
authors.initials: J
authors.lastname: Martinez-Picado
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology*; D004279:DNA, Viral / Q000235:genetics; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D010802:Phylogeny; D011533:Proviruses / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000821:virology; D019562:Viral Load; D056189:Viral Tropism; D014766:Viremia / Q000821:virology*
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D012367:RNA, Viral
keywords: CD4+ T cell subsets; HIV-1; Persistence; Residual viremia; Viral reservoir