Frequencies of Gag-restricted T-cell escape "footprints" differ across HIV-1 clades A1 and D chronically infected Ugandans irrespective of host HLA B alleles.
OBJECTIVE
We evaluated relationships between critical Gag T-cell escape mutations and concomitant T-cell responses to determine whether HLA-restricted Gag mutations that confer protection, occur at similar rates in a population infected with mixed HIV-1 clades A1 and D viruses.


METHODS
Assessment of Gag selective pressure, and adaptive T-cell functions to KAFSPEVIPMF (KF11), ISPRTLNAW (ISW9) and TSTLQEQIGW (TW10) Gag epitopes were combined with host HLA to assess correlations with rates of critical epitope escape mutations in clades A1- (n=23) and D- (n=21) infected, untreated subjects. Infecting clades and selection pressure were determined from the gag sequences.


RESULTS
Overall, Gag escape mutations A163X in KF11 were detected in 61% (14/23) A1- infected compared to 5% (1/21) in D-infected subjects (p=0.00015). Gag mutations I147X in the ISW9 epitope were seen in 43%: (10/23) clade A compared to 5%: (1/21) clade D infected subjects, p=0.007, Fisher's Exact test. Both mutations were more frequent in clade A1 infection. Frequencies of the measured epitope-specific T-cell responses were comparable across clades. Peptide binding affinities for the restricting HLA alleles did not differ across clades. Overall, selection pressure on the Gag protein was significantly greater in clade A than in clade D sequences.


CONCLUSIONS
These findings imply that HIV-1 vaccine strategies designed to target structurally constrained T-cell epitopes may be further challenged by clade-driven outcomes in specific HLA-restricted Gag epitopes. Equally, the data are line with slower HIV-1 disease progression in clade A infection; and raise hope that increased selective pressure on Gag may be protective irrespective of host HLA alleles.
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda. Electronic address: jennifer.serwanga@mrcuganda.org.
Jennifer
J
Serwanga
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
Ritah
R
Nakiboneka
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
Susan
S
Mugaba
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
Brian
B
Magambo
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
Nicaise
N
Ndembi
Department of Immunology, Imperial College, Chelsea & Westminster Hospital, London, United Kingdom.
Frances
F
Gotch
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda; London School of Hygiene and Tropical Medicine, United Kingdom.
Pontiano
P
Kaleebu
D016915:AIDS Vaccines; D000328:Adult; D000483:Alleles; D044383:Black People / Q000235:genetics; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D005805:Genes, MHC Class I; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012641:Selection, Genetic; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014454:Uganda; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016915:AIDS Vaccines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma
Clades A1 and D; Escape mutations; Gag; HIV-1; HLA B alleles; Selection pressure