PMID- 18580606
OWN - NLM
STAT- MEDLINE
DCOM- 20080821
LR  - 20080626
IS  - 1473-5571 (Electronic)
IS  - 0269-9370 (Linking)
VI  - 22
IP  - 11
DP  - 2008 Jul 11
TI  - Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association 
      with viral load in chronic untreated infection.
PG  - 1277-86
LID - 10.1097/QAD.0b013e3283021a8c [doi]
AB  - OBJECTIVE: Selection of specific human leukocyte antigen (HLA)-restricted 
      cytotoxic T-lymphocyte (CTL) escape mutations in key Gag epitopes has been 
      associated with loss of HIV immune control on an individual basis. Here we 
      undertake a population-based identification of HLA-associated polymorphisms in 
      Gag and investigate their relationship with plasma viral load. DESIGN: 
      Cross-sectional analysis of 567 chronically HIV subtype B-infected, 
      treatment-naive individuals. METHODS: HLA class I-associated Gag substitutions 
      were identified using phylogenetically corrected analysis methods featuring a 
      multivariate adjustment for HLA linkage disequilibrium and a q-value correction 
      for multiple tests. Presence of HLA-associated substitutions and markers of HIV 
      disease status were correlated using Spearman's rank test. RESULTS: We have 
      created a gene-wide map of HLA class I-associated substitutions in HIV-1 subtype 
      B Gag. This features 111 HLA-associated substitutions occurring at 51 of 500 Gag 
      codons, more than 50% of which occur within published and/or putative 
      HLA-restricted CTL epitopes. A modest inverse correlation was observed between 
      the total number of HLA-associated Gag polymorphic sites within each individual 
      and plasma viral load in chronic untreated infection (R = -0.17, P < 0.0001), 
      supporting the hypothesis that a broad ability to target Gag in vivo contributes 
      to viral control. A modest positive correlation was observed between the 
      proportion of these sites exhibiting HLA-associated substitutions and plasma 
      viral load (R = 0.09, P = 0.03), consistent with a loss of viremia control with 
      the accumulation of CTL escape mutations. CONCLUSION: Results contribute to our 
      understanding of immune-driven viral adaptation and suggest that the accumulation 
      of CTL escape mutations in Gag results in clinically detectable consequences at 
      the population level. These data have implications for HIV vaccines.
FAU - Brumme, Zabrina L
AU  - Brumme ZL
AD  - Partners AIDS Research Center, Massachusetts General Hospital, Boston, Harvard 
      Medical School, Massachusetts 02129, USA.
FAU - Tao, Iris
AU  - Tao I
FAU - Szeto, Sharon
AU  - Szeto S
FAU - Brumme, Chanson J
AU  - Brumme CJ
FAU - Carlson, Jonathan M
AU  - Carlson JM
FAU - Chan, Dennison
AU  - Chan D
FAU - Kadie, Carl
AU  - Kadie C
FAU - Frahm, Nicole
AU  - Frahm N
FAU - Brander, Christian
AU  - Brander C
FAU - Walker, Bruce
AU  - Walker B
FAU - Heckerman, David
AU  - Heckerman D
FAU - Harrigan, P Richard
AU  - Harrigan PR
LA  - eng
GR  - N01-AL-15422/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - AIDS
JT  - AIDS (London, England)
JID - 8710219
RN  - 0 (gag Gene Products, Human Immunodeficiency Virus)
SB  - IM
MH  - Amino Acid Sequence
MH  - CD4 Lymphocyte Count
MH  - Chronic Disease
MH  - Cross-Sectional Studies
MH  - Genes, MHC Class I/genetics
MH  - HIV Infections/immunology/*virology
MH  - HIV-1/*genetics
MH  - Humans
MH  - Molecular Sequence Data
MH  - *Polymorphism, Genetic
MH  - T-Lymphocytes, Cytotoxic/immunology
MH  - Viral Load
MH  - gag Gene Products, Human Immunodeficiency Virus/*genetics
EDAT- 2008/06/27 09:00
MHDA- 2008/08/22 09:00
CRDT- 2008/06/27 09:00
PHST- 2008/06/27 09:00 [pubmed]
PHST- 2008/08/22 09:00 [medline]
PHST- 2008/06/27 09:00 [entrez]
AID - 00002030-200807110-00004 [pii]
AID - 10.1097/QAD.0b013e3283021a8c [doi]
PST - ppublish
SO  - AIDS. 2008 Jul 11;22(11):1277-86. doi: 10.1097/QAD.0b013e3283021a8c.