PMID- 23797286
OWN - NLM
STAT- MEDLINE
DCOM- 20140617
LR  - 20151119
IS  - 1537-6591 (Electronic)
IS  - 1058-4838 (Linking)
VI  - 57
IP  - 7
DP  - 2013 Oct
TI  - Naturally selected rilpivirine-resistant HIV-1 variants by host cellular 
      immunity.
PG  - 1051-5
LID - 10.1093/cid/cit430 [doi]
AB  - BACKGROUND: Rilpivirine is listed as an alternative key drug in current 
      antiretroviral therapy (ART) guidelines. E138G/A/K in human immunodeficiency 
      virus type 1 (HIV-1) reverse transcriptase (RT) are rilpivirine 
      resistance-associated mutations and can be identified in a few ART-naive 
      patients, although at low frequency. The 138th position in HIV-1 RT is located in 
      one of the putative epitopes of human leukocyte antigen (HLA)-B*18-restricted 
      cytotoxic T lymphocytes (CTLs). CTL-mediated immune pressure selects escape 
      mutations within the CTL epitope. Here we tested whether E138G/A/K could be 
      selected by HLA-B*18-restricted CTLs. METHODS: The amino acid variation at the 
      138th position was compared between ART-naive HIV-1-infected patients with and 
      without HLA-B*18. The optimal epitope containing the 138th position was 
      determined and the impact of E138G/A/K on CTL response was analyzed by 
      epitope-specific CTLs. The effect of E138G/A/K on drug susceptibility was 
      determined by constructing recombinant HIV-1 variants. RESULTS: The prevalence of 
      E138G/A/K was 21% and 0.37% in 19 and 1088 patients with and without HLA-B*18, 
      respectively (odds ratio, 72.3; P = 4.9 x 10(-25)). The CTL response was 
      completely abolished by the substitution of E138G/A/K in the epitope peptide. 
      E138G/A/K conferred 5.1-, 7.1-, and 2.7-fold resistance to rilpivirine, 
      respectively. CONCLUSIONS: E138G/A/K can be selected by HLA-B*18-restricted CTLs 
      and confer significant rilpivirine resistance. We recommend drug resistance 
      testing before the introduction of rilpivirine-based ART in HLA-B*18-positive 
      patients.
FAU - Gatanaga, Hiroyuki
AU  - Gatanaga H
AD  - AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo.
FAU - Murakoshi, Hayato
AU  - Murakoshi H
FAU - Hachiya, Atsuko
AU  - Hachiya A
FAU - Hayashida, Tsunefusa
AU  - Hayashida T
FAU - Chikata, Takayuki
AU  - Chikata T
FAU - Ode, Hirotaka
AU  - Ode H
FAU - Tsuchiya, Kiyoto
AU  - Tsuchiya K
FAU - Sugiura, Wataru
AU  - Sugiura W
FAU - Takiguchi, Masafumi
AU  - Takiguchi M
FAU - Oka, Shinichi
AU  - Oka S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130623
PL  - United States
TA  - Clin Infect Dis
JT  - Clinical infectious diseases : an official publication of the Infectious Diseases 
      Society of America
JID - 9203213
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-B18 Antigen)
RN  - 0 (Nitriles)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1)
RN  - EC 2.7.7.49 (HIV Reverse Transcriptase)
RN  - FI96A8X663 (Rilpivirine)
SB  - IM
MH  - Anti-HIV Agents/*pharmacology
MH  - Drug Resistance, Viral/genetics
MH  - Epitopes, T-Lymphocyte/*genetics
MH  - HIV Infections/*immunology/*virology
MH  - HIV Reverse Transcriptase/genetics
MH  - HIV-1/*drug effects/genetics/immunology
MH  - HLA-B18 Antigen/genetics/immunology
MH  - Host-Pathogen Interactions/genetics/immunology
MH  - Humans
MH  - Leukocytes, Mononuclear/immunology
MH  - Models, Molecular
MH  - Mutation
MH  - Nitriles/*pharmacology
MH  - Pyrimidines/*pharmacology
MH  - Rilpivirine
MH  - T-Lymphocytes, Cytotoxic/immunology
OTO - NOTNLM
OT  - CTL
OT  - E138G/A/K
OT  - HLA-B*18
OT  - rilpivirine
EDAT- 2013/06/26 06:00
MHDA- 2014/06/18 06:00
CRDT- 2013/06/26 06:00
PHST- 2013/06/26 06:00 [entrez]
PHST- 2013/06/26 06:00 [pubmed]
PHST- 2014/06/18 06:00 [medline]
AID - cit430 [pii]
AID - 10.1093/cid/cit430 [doi]
PST - ppublish
SO  - Clin Infect Dis. 2013 Oct;57(7):1051-5. doi: 10.1093/cid/cit430. Epub 2013 Jun 
      23.