An integrative bioinformatic approach for studying escape mutations in human immunodeficiency virus type 1 gag in the Pumwani Sex Worker Cohort.
Human immunodeficiency virus type 1 (HIV-1) is able to evade the host cytotoxic T-lymphocyte (CTL) response through a variety of escape avenues. Epitopes that are presented to CTLs are first processed in the presenting cell in several steps, including proteasomal cleavage, transport to the endoplasmic reticulum, binding by the HLA molecule, and finally presentation to the T-cell receptor. An understanding of the potential of the virus to escape CTL responses can aid in designing an effective vaccine. To investigate such a potential, we analyzed HIV-1 gag from 468 HIV-1-positive Kenyan women by using several bioinformatic approaches that allowed the identification of positively selected amino acids in the HIV-1 gag region and study of the effects that these mutations could have on the various stages of antigen processing. Correlations between positively selected residues and mean CD4 counts also allowed study of the effect of mutation on HIV disease progression. A number of mutations that could create or destroy proteasomal cleavage sites or reduce binding affinity of the transport antigen processing protein, effectively hindering epitope presentation, were identified. Many mutations correlated with the presence of specific HLA alleles and with lower or higher CD4 counts. For instance, the mutation V190I in subtype A1-infected individuals is associated with HLA-B*5802 (P = 4.73 x 10(-4)), a rapid-progression allele according to other studies, and also to a decreased mean CD4 count (P = 0.019). Thus, V190I is a possible HLA escape mutant. This method classifies many positively selected mutations across the entire gag region according to their potential for immune escape and their effect on disease progression.
National Microbiology Laboratory, 1015 Arlington St., Winnipeg, Manitoba R3E 3R2, Canada.
Harold O
HO
Peters
Mark G
MG
Mendoza
Rupert E
RE
Capina
Ma
M
Luo
Xiaojuan
X
Mao
Michael
M
Gubbins
Nico J D
NJ
Nagelkerke
Ian
I
Macarthur
Brent B
BB
Sheardown
Joshua
J
Kimani
Charles
C
Wachihi
Subo
S
Thavaneswaran
Francis A
FA
Plummer
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015331:Cohort Studies; D019295:Computational Biology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007109:Immunity; D007630:Kenya; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D011477:Sex Work; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000145:classification / Q000235:genetics*
D000939:Epitopes; D006680:HLA Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus; D046988:Proteasome Endopeptidase Complex