title: Differential impact of APOBEC3-driven mutagenesis on HIV evolution in diverse anatomical compartments.
abstract: OBJECTIVE
  Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure.
  
  
  METHODS
  To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day.
  
  
  RESULTS
  APOBEC3-mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients' CSF (i.e. G73S in protease; M184I, M230I in reverse transcriptase) and two other patients' rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells.
  
  
  CONCLUSIONS
  APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART.
authors.affiliation: aInserm UMR S-943 bVirology Department cInfectious Disease Department dInternal Medicine Department, Pitie-Salpetriere Hospital eUniversité Pierre and Marie Curie fInserm UMR S945 gAP-HP hImmunology Department, Pitie-Salpetriere Hospital, Paris, France.
authors.forename: Slim
authors.initials: S
authors.lastname: Fourati
authors.forename: Sidonie
authors.initials: S
authors.lastname: Lambert-Niclot
authors.forename: Cathia
authors.initials: C
authors.lastname: Soulie
authors.forename: Marc
authors.initials: M
authors.lastname: Wirden
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Marc A
authors.initials: MA
authors.lastname: Valantin
authors.forename: Roland
authors.initials: R
authors.lastname: Tubiana
authors.forename: Anne
authors.initials: A
authors.lastname: Simon
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Guislaine
authors.initials: G
authors.lastname: Carcelain
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
mesh_terms: D000071478:APOBEC Deaminases; D001826:Body Fluids / Q000821:virology; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000276:immunology*; D019143:Evolution, Molecular; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics; D012641:Selection, Genetic; D014779:Virus Replication
chemical_list: D012367:RNA, Viral; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase