PMID- 19918099
OWN - NLM
STAT- MEDLINE
DCOM- 20100203
LR  - 20211020
IS  - 1359-6535 (Print)
IS  - 2040-2058 (Electronic)
IS  - 1359-6535 (Linking)
VI  - 14
IP  - 7
DP  - 2009
TI  - Effects of HIV type-1 immune selection on susceptability to integrase inhibitor 
      resistance.
PG  - 953-64
LID - 10.3851/IMP1419 [doi]
AB  - BACKGROUND: All site-specific interactions between HIV type-1 (HIV-1) subtype, 
      human leukocyte antigen (HLA)-associated immune selection and integrase inhibitor 
      resistance are not completely understood. We examined naturally occurring 
      polymorphisms in HIV-1 integrase sequences from 342 antiretroviral-naive 
      individuals from the Western Australian HIV Cohort Study and the Swiss HIV Cohort 
      Study. METHODS: Standard bulk sequencing and sequence-based typing were used to 
      generate integrase sequences and high-resolution HLA genotypes, respectively. 
      Viral residues were examined with respect to drug resistance mutations and CD8(+) 
      T-cell escape mutations. RESULTS: In both predominantly subtype B cohorts, 12 of 
      38 sites that mediate integrase inhibitor resistance mutations were absolutely 
      conserved, and these included the primary resistance mutations. There were 18 
      codons with non-primary drug resistance-associated substitutions at rates of up 
      to 58.8% and eight sites with alternative polymorphisms. Five viral residues were 
      potentially subject to dual-drug and HLA-associated immune selection in which 
      both selective pressures either drove the same amino acid substitution (codons 
      72, 157 and 163) or HLA alleles were associated with an alternative polymorphism 
      that would alter the genetic barrier to resistance (codons 125 and 193). The 
      common polymorphism T125A, which was characteristic of non-subtype B and was also 
      associated with carriage of HLA-B*57/*5801, increased the mutational barrier to 
      the resistance mutation T125K. CONCLUSIONS: Primary integrase inhibitor 
      resistance mutations were not detected in the absence of drug exposure in keeping 
      with sites of high constraint. Viral polymorphisms caused by immune selection 
      and/or associated with non-subtype B might alter the genetic barrier to some 
      non-primary resistance-associated mutations.
FAU - Tschochner, Monika
AU  - Tschochner M
AD  - Institute for Immunology and Infectious Diseases, Royal Perth Hospital and 
      Murdoch University, Perth, Australia.
FAU - Chopra, Abha
AU  - Chopra A
FAU - Maiden, Tanya M
AU  - Maiden TM
FAU - Ahmad, Imran F
AU  - Ahmad IF
FAU - James, Ian
AU  - James I
FAU - Furrer, Hansjakob
AU  - Furrer H
FAU - Gunthard, Huldrych F
AU  - Gunthard HF
FAU - Mallal, Simon
AU  - Mallal S
FAU - Rauch, Andri
AU  - Rauch A
FAU - John, Mina
AU  - John M
LA  - eng
GR  - P30 AI110527/AI/NIAID NIH HHS/United States
GR  - R01 AI060460/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Antivir Ther
JT  - Antiviral therapy
JID - 9815705
RN  - 0 (HIV Integrase Inhibitors)
RN  - 0 (HLA Antigens)
RN  - 0 (RNA, Viral)
RN  - EC 2.7.7.- (HIV Integrase)
SB  - IM
MH  - Amino Acid Sequence
MH  - *Drug Resistance, Viral/genetics/immunology
MH  - HIV Infections/*drug therapy/*immunology/virology
MH  - HIV Integrase/genetics/*immunology
MH  - HIV Integrase Inhibitors/*therapeutic use
MH  - HIV-1/*drug effects/genetics/*immunology
MH  - HLA Antigens/immunology
MH  - Humans
MH  - Molecular Sequence Data
MH  - Polymorphism, Genetic/immunology
MH  - RNA, Viral/analysis/genetics
MH  - Sequence Analysis, DNA
MH  - Viral Load
PMC - PMC4155129
MID - NIHMS569600
EDAT- 2009/11/18 06:00
MHDA- 2010/02/04 06:00
PMCR- 2014/09/05
CRDT- 2009/11/18 06:00
PHST- 2009/11/18 06:00 [entrez]
PHST- 2009/11/18 06:00 [pubmed]
PHST- 2010/02/04 06:00 [medline]
PHST- 2014/09/05 00:00 [pmc-release]
AID - 10.3851/IMP1419 [doi]
PST - ppublish
SO  - Antivir Ther. 2009;14(7):953-64. doi: 10.3851/IMP1419.