PMID- 17804494
OWN - NLM
STAT- MEDLINE
DCOM- 20071212
LR  - 20220317
IS  - 0022-538X (Print)
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 81
IP  - 22
DP  - 2007 Nov
TI  - Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in 
      Gag is associated with a dramatic reduction in human immunodeficiency virus type 
      1 replication.
PG  - 12382-93
AB  - Human leukocyte antigen (HLA)-B27-positive subjects are uncommon in their ability 
      to control infection with human immunodeficiency virus type 1 (HIV-1). However, 
      late viral escape from a narrowly directed immunodominant Gag-specific CD8(+) 
      T-lymphocyte (CTL) response has been linked to AIDS progression in these 
      individuals. Identifying the mechanism of the immune-mediated control may provide 
      critical insights into HIV-1 vaccine development. Here, we illustrate that the 
      CTL escape mutation R(264)K in the HLA-B27-restricted KK10 epitope in the capsid 
      resulted in a significant defect in viral replication in vitro. The R(264)K 
      variant was impaired in generating late reverse transcription products, 
      indicating that replication was blocked at a postentry step. Notably, the R(264)K 
      mutation was associated in vivo with the development of a rare secondary 
      mutation, S(173)A, which restored viral replication in vitro. Furthermore, 
      infectivity of the R(264)K variant was rescued by the addition of cyclosporine A 
      or infection of a cyclophilin A-deficient cell line. These data demonstrate a 
      severe functional defect imposed by the R(264)K mutation during an early step in 
      viral replication that is likely due to the inability of this variant to 
      replicate efficiently in the presence of normal levels of cyclophilin A. We 
      conclude that the impact of the R(264)K substitution on capsid structure 
      constrains viral escape and enables long-term maintenance of the dominant CTL 
      response against B27-KK10, providing an explanation for the protective effect of 
      HLA-B27 during HIV infection.
FAU - Schneidewind, Arne
AU  - Schneidewind A
AD  - Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical 
      School, Boston, MA, USA.
FAU - Brockman, Mark A
AU  - Brockman MA
FAU - Yang, Ruifeng
AU  - Yang R
FAU - Adam, Rahma I
AU  - Adam RI
FAU - Li, Bin
AU  - Li B
FAU - Le Gall, Sylvie
AU  - Le Gall S
FAU - Rinaldo, Charles R
AU  - Rinaldo CR
FAU - Craggs, Sharon L
AU  - Craggs SL
FAU - Allgaier, Rachel L
AU  - Allgaier RL
FAU - Power, Karen A
AU  - Power KA
FAU - Kuntzen, Thomas
AU  - Kuntzen T
FAU - Tung, Chang-Shung
AU  - Tung CS
FAU - LaBute, Montiago X
AU  - LaBute MX
FAU - Mueller, Sandra M
AU  - Mueller SM
FAU - Harrer, Thomas
AU  - Harrer T
FAU - McMichael, Andrew J
AU  - McMichael AJ
FAU - Goulder, Philip J R
AU  - Goulder PJ
FAU - Aiken, Christopher
AU  - Aiken C
FAU - Brander, Christian
AU  - Brander C
FAU - Kelleher, Anthony D
AU  - Kelleher AD
FAU - Allen, Todd M
AU  - Allen TM
LA  - eng
GR  - R21 AI067078/AI/NIAID NIH HHS/United States
GR  - MC_U137884177/MRC_/Medical Research Council/United Kingdom
GR  - R01 AI050423/AI/NIAID NIH HHS/United States
GR  - R01 AI054178/AI/NIAID NIH HHS/United States
GR  - U01 AI052403/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070905
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (HLA-B27 Antigen)
RN  - 0 (Immunodominant Epitopes)
RN  - 0 (gag Gene Products, Human Immunodeficiency Virus)
RN  - 83HN0GTJ6D (Cyclosporine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Capsid/immunology
MH  - Cyclosporine/pharmacology
MH  - HIV Infections/*immunology
MH  - HIV-1/genetics/*physiology
MH  - HLA-B27 Antigen/analysis/*immunology
MH  - Humans
MH  - Immunodominant Epitopes/*genetics/immunology
MH  - Molecular Sequence Data
MH  - Mutation
MH  - T-Lymphocytes, Cytotoxic/*immunology
MH  - Virus Replication/genetics
MH  - gag Gene Products, Human Immunodeficiency Virus/*genetics/immunology
PMC - PMC2169010
EDAT- 2007/09/07 09:00
MHDA- 2007/12/13 09:00
PMCR- 2008/03/01
CRDT- 2007/09/07 09:00
PHST- 2007/09/07 09:00 [pubmed]
PHST- 2007/12/13 09:00 [medline]
PHST- 2007/09/07 09:00 [entrez]
PHST- 2008/03/01 00:00 [pmc-release]
AID - JVI.01543-07 [pii]
AID - 1543-07 [pii]
AID - 10.1128/JVI.01543-07 [doi]
PST - ppublish
SO  - J Virol. 2007 Nov;81(22):12382-93. doi: 10.1128/JVI.01543-07. Epub 2007 Sep 5.