title: Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure.
abstract: The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.
authors.affiliation: National Reference Center for AIDS, Department of Microbiology, School of Medicine, University of Buenos Aires, Argentina.
authors.forename: Gustavo H
authors.initials: GH
authors.lastname: Kijak
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.forename: Peter
authors.initials: P
authors.lastname: Balfe
authors.forename: Jeroen
authors.initials: J
authors.lastname: Vanderhoeven
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Pampuro
authors.forename: Carlos
authors.initials: C
authors.lastname: Zala
authors.forename: Claudia
authors.initials: C
authors.lastname: Ochoa
authors.forename: Pedro
authors.initials: P
authors.lastname: Cahn
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Horacio
authors.initials: H
authors.lastname: Salomon
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D015686:Gene Products, env / Q000235:genetics; D015684:Gene Products, pol / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents; D015686:Gene Products, env; D015684:Gene Products, pol; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease