title: Therapeutic Immune Recovery and Reduction of CXCR4-Tropic HIV-1.
abstract: BACKGROUND
  In the absence of therapy, CXCR4 (X4)-tropic human immunodeficiency virus type 1 (HIV-1) increases over time, associated with accelerated disease progression. In contrast, the majority of patients receiving long-term combination antiretroviral therapy (cART) present with CCR5 (R5)-tropic HIV-1 variants. It is unclear whether cART itself mediates the reduction of X4-tropic HIV-1. The current study aimed at assessing the tropism of viral integrates in patients' blood during fully suppressive cART.
  
  
  METHODS
  The relative frequencies of X4-tropic proviral HIV-1 variants were determined by means of next-generation sequencing (False Positive Rate (FPR), 3.5%; R5- or X4 tropic variants occurring at less than 2% of the total virus population) for 35 treated patients in the Swiss HIV Cohort Study and followed longitudinally over time. Full viral suppression and a continuous CD4 T-cell recovery during cART were documented for all patients. Viral phylogenetic changes and sequence evolution were analyzed.
  
  
  RESULTS
  The majority of patients (80%) experienced no frequency increase in X4-tropic proviruses during therapy. Although some proviral sequence evolution was demonstrable in >50% of these patients during therapy, this growing viral diversity was in no case paralleled by the emergence or expansion of X4-tropic provirus variants. In the remaining 20% of patients, the documented expansion of X4-tropic provirus was based on the outgrowth of single viral variants from minority populations already present before therapy initiation.
  
  
  CONCLUSIONS
  Our study demonstrates that X4-tropic HIV sharply declines in most patients during successful therapy, which indicates a preferential tropism-dependent provirus elimination in the immunocompetent host. The recently implemented World Health Organization strategies of immediate therapy initiation are fully in line with this gradual loss of X4 tropism during therapy. Moreover, the early use of coreceptor antagonists against the remaining CCR5-tropic viruses may be indicated.
authors.affiliation: Molecular Virology, Department of Biomedicine-Petersplatz, University of Basel.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Bader
authors.affiliation: Institute for Immunogenetics, Kaiserslautern, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Däumer
authors.affiliation: Swiss HIV Cohort Study Data Center, University Hospital Lausanne.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schöni-Affolter
authors.affiliation: Institute of Medical Virology, National Center for Retroviruses, University of Zürich.
authors.forename: Jürg
authors.initials: J
authors.lastname: Böni
authors.affiliation: Institute for Infectious Diseases, University of Berne.
authors.forename: Meri
authors.initials: M
authors.lastname: Gorgievski-Hrisoho
authors.affiliation: Department of Microbiology, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
authors.forename: Gladys
authors.initials: G
authors.lastname: Martinetti
authors.affiliation: Max Planck Institute for Informatics, Saarbrücken, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Thielen
authors.affiliation: Molecular Virology, Department of Biomedicine-Petersplatz, University of Basel, thomas.klimkait@unibas.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020010:Heterosexuality; D018451:Homosexuality, Male; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology*; D000072230:Sustained Virologic Response; D019562:Viral Load; D056189:Viral Tropism / Q000187:drug effects / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D019713:Receptors, CCR5; D019718:Receptors, CXCR4
keywords: CXCR4-tropic; HIV; immune system.; tropism