PMID- 24740510
OWN - NLM
STAT- MEDLINE
DCOM- 20140624
LR  - 20211021
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 192
IP  - 10
DP  - 2014 May 15
TI  - Functional avidity and IL-2/perforin production is linked to the emergence of 
      mutations within HLA-B*5701-restricted epitopes and HIV-1 disease progression.
PG  - 4685-96
LID - 10.4049/jimmunol.1302253 [doi]
AB  - Viral escape from HIV-1-specific CD8(+) T cells has been demonstrated in numerous 
      studies previously. However, the qualitative features driving the emergence of 
      mutations within epitopes are still unclear. In this study, we aimed to 
      distinguish whether specific functional characteristics of HLA-B*5701-restricted 
      CD8(+) T cells influence the emergence of mutations in high-risk progressors 
      (HRPs) versus low-risk progressors (LRPs). Single-genome sequencing was performed 
      to detect viral mutations (variants) within seven HLA-B*5701-restricted epitopes 
      in Gag (n = 4) and Nef (n = 3) in six untreated HLA-B*5701 subjects followed from 
      early infection up to 7 y. Several well-characterized effector markers (IFN-gamma, 
      IL-2, MIP-1beta, TNF, CD107a, and perforin) were identified by flow cytometry 
      following autologous (initial and emerging variant/s) epitope stimulations. This 
      study demonstrates that specific functional attributes may facilitate the 
      outgrowth of mutations within HLA-B*5701-restricted epitopes. A significantly 
      lower fraction of IL-2-producing cells and a decrease in functional avidity and 
      polyfunctional sensitivity were evident in emerging epitope variants compared 
      with the initial autologous epitopes. Interestingly, the HRPs mainly drove these 
      differences, whereas the LRPs maintained a directed and maintained functional 
      response against emerging epitope variants. In addition, LRPs induced improved 
      cell-cycle progression and perforin upregulation after autologous and emerging 
      epitope variant stimulations in contrast to HRPs. The maintained quantitative and 
      qualitative features of the CD8(+) T cell responses in LRPs toward emerging 
      epitope variants provide insights into why HLA-B*5701 subjects have different 
      risks of HIV-1 disease progression.
FAU - Buggert, Marcus
AU  - Buggert M
AD  - Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska 
      Institutet, Stockholm S-141 86, Sweden;
FAU - Norstrom, Melissa M
AU  - Norstrom MM
FAU - Salemi, Marco
AU  - Salemi M
FAU - Hecht, Frederick M
AU  - Hecht FM
FAU - Karlsson, Annika C
AU  - Karlsson AC
LA  - eng
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GR  - K24 AT007827/AT/NCCIH NIH HHS/United States
GR  - P01 AI071713/AI/NIAID NIH HHS/United States
GR  - P30 AI027763/AI/NIAID NIH HHS/United States
PT  - Clinical Trial
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140416
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Cytokines)
RN  - 0 (Epitopes)
RN  - 0 (Gene Products, gag)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B*57:01 antigen)
RN  - 0 (IL2 protein, human)
RN  - 0 (Interleukin-2)
RN  - 126465-35-8 (Perforin)
SB  - IM
MH  - Base Sequence
MH  - Cell Cycle/genetics/immunology
MH  - Cytokines/genetics/immunology/metabolism
MH  - Disease Progression
MH  - Epitopes/genetics/*immunology/metabolism
MH  - Gene Products, gag/genetics/*immunology/metabolism
MH  - HIV Infections/genetics/*immunology/metabolism/pathology
MH  - HIV-1/genetics/*immunology/metabolism
MH  - HLA-B Antigens/genetics/*immunology/metabolism
MH  - Humans
MH  - Interleukin-2/biosynthesis/genetics/*immunology
MH  - Male
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Perforin/biosynthesis/genetics/*immunology
MH  - Up-Regulation/genetics/immunology
PMC - PMC4046013
MID - NIHMS576809
EDAT- 2014/04/18 06:00
MHDA- 2014/06/25 06:00
PMCR- 2015/05/15
CRDT- 2014/04/18 06:00
PHST- 2014/04/18 06:00 [entrez]
PHST- 2014/04/18 06:00 [pubmed]
PHST- 2014/06/25 06:00 [medline]
PHST- 2015/05/15 00:00 [pmc-release]
AID - jimmunol.1302253 [pii]
AID - 10.4049/jimmunol.1302253 [doi]
PST - ppublish
SO  - J Immunol. 2014 May 15;192(10):4685-96. doi: 10.4049/jimmunol.1302253. Epub 2014 
      Apr 16.