title: Protease inhibitor-resistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes.
abstract: OBJECTIVE
  To evaluate CD4 T-cell cytopathicity of protease inhibitor (PI)-resistant isolates from patients with preserved CD4 cell counts after long-term virologic failure.
  
  
  METHODS
  PI-resistant primary isolates from 14 patients with stable or increasing CD4 T-cell counts despite long-term virologic failure during continuous combination therapy were examined. Replication and cytopathicity were assessed in activated peripheral blood mononuclear cell cultures in the presence and absence of PI using titered stocks of primary HIV-1 isolates and during initial viral isolation. Also studied were PI-sensitive isolates from four of these patients after therapy discontinuation and reversion to PI-sensitive virus and from seven antiretroviral drug-naive patients. Coreceptor use, syncytia-inducing (SI) phenotype and protease sequences were determined by standard methods.
  
  
  RESULTS
  All isolates obtained during continued therapy showed genetic markers of PI resistance and decreased phenotypic susceptibility. PI-resistant SI isolates were highly to moderately cytopathic whereas non-syncytia-inducing isolates were moderately to weakly cytopathic. PI-susceptible and PI-resistant isolates obtained after discontinuation of therapy were equally cytopathic at similar replication levels. The cytopathicity of PI-resistant isolates was not altered by PI and was similar to that of isolates from untreated subjects.
  
  
  CONCLUSIONS
  Primary isolates from patients showing virologic rebound without net CD4 T-cell loss during continued therapy are as cytopathic as PI-sensitive isolates with equivalent input infectious titer. As with PI-sensitive isolates, cytopathicity of PI-resistant viruses was determined primarily by coreceptor preference. These results suggest that the sustained immunologic response observed after failure of PI-containing regimens is not due to the emergence of PI-resistant strains that are intrinsically less cytopathic for activated peripheral CD4 lymphocytes.
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, California 94141-9100, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Liegler
authors.forename: M S
authors.initials: MS
authors.lastname: Hayden
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Hoh
authors.forename: S G
authors.initials: SG
authors.lastname: Deeks
authors.forename: R M
authors.initials: RM
authors.lastname: Granta
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D003430:Cross-Sectional Studies; D003588:Cytopathogenic Effect, Viral; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D008213:Lymphocyte Activation
chemical_list: D017320:HIV Protease Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease