title: Drug resistance and viral evolution in plasma and peripheral blood cells during structured treatment interruption (STI) and non-interrupted HAART.
abstract: BACKGROUND
  Highly active antiretroviral therapy (HAART) can successfully reduce plasma and tissue levels of HIV-1 RNA and results in reductions in HIV-related morbidity and mortality, but the slow viral evolution during therapy in cellular reservoirs is a continuing problem. In addition, little remains known how viral evolutionary process may differ between cell-free and cell-associated compartments, over time, in vivo in patients receiving HAART or STI.
  
  
  OBJECTIVE
  The main objectives of this study were to assess viral replication kinetics, drug resistance and viral evolution during HAART and STI.
  
  
  METHODS
  We have conducted a longitudinal study of virus culture kinetics in vitro, molecular analysis of uncultured HIV-1 variants from plasma and PBMC of 6 patients on HAART, 4 patients on STI, and 6 from treatment-naïve patients.
  
  
  RESULTS
  Our data suggest that drug resistance mutations remained compartmentalized between plasma and PBMC. The divergent distribution of resistance mutations between plasma and PBMC coincided with divergent env gene evolution in these compartments. In contrast, the HIV strains from therapy-naive patients showed tight genetic and phylogenetic concordance between plasma and PBMC. Both STI and non-STI groups showed the presence of resistance mutations to both RT and protease inhibitors, which correlated with inadequate suppression of viremia and partially with the virus culture isolation in vitro.
  
  
  CONCLUSIONS
  Overall, STI for HIV patients has no added advantage over regular HAART at the virologic level and in the diminution of resistance mutations that result in therapy failure. Under both forms of anti-retroviral therapies, virus could be isolated in vitro from the PBMC showing continuing low-level viral replication under suppressive therapy. Overall, these data may be useful in predicting the late emergence of drug resistance mutations via the latent integrated provirus.
authors.affiliation: Retroviral Genetics Laboratory, Centre for Virus Research, Westmead Millennium Institutes, Westmead Hospital, The University of Sydney, Sydney, Australia.
authors.forename: Yuan Min
authors.initials: YM
authors.lastname: Wang
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Dyer
authors.forename: Cassy
authors.initials: C
authors.lastname: Workman
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Ng Kee
authors.initials: NK
authors.lastname: Peng
authors.forename: Kishen
authors.initials: K
authors.lastname: Lachireddy
authors.forename: Choo Beng
authors.initials: CB
authors.lastname: Chew
authors.forename: John
authors.initials: J
authors.lastname: Sullivan
authors.forename: Nitin K
authors.initials: NK
authors.lastname: Saksena
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018929:Cell Culture Techniques; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000187:drug effects / Q000235:genetics; D015752:Genes, env / Q000187:drug effects; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D010949:Plasma / Q000821:virology*; D020539:Sequence Analysis, Protein; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D015686:Gene Products, env; D054303:HIV Reverse Transcriptase; D016333:HIV Protease