Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection.
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.


METHODS
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.


CONCLUSIONS
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.
Brumme
Zabrina L
ZL
Partners AIDS Research Center, Massachusetts General Hospital, Boston, Harvard Medical School, Massachusetts 02129, USA.
Tao
Iris
I
Szeto
Sharon
S
Brumme
Chanson J
CJ
Carlson
Jonathan M
JM
Chan
Dennison
D
Kadie
Carl
C
Frahm
Nicole
N
Brander
Christian
C
Walker
Bruce
B
Heckerman
David
D
Harrigan
P Richard
PR
D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D005805:Genes, MHC Class I / Q000235:genetics; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D054301:gag Gene Products, Human Immunodeficiency Virus