Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA.
Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
Leslie
Alasdair
A
Peter Medawar Building, University of Oxford, Oxford OX13SY, UK.
Kavanagh
Daniel
D
Honeyborne
Isobella
I
Pfafferott
Katja
K
Edwards
Charles
C
Pillay
Tilly
T
Hilton
Louise
L
Thobakgale
Christina
C
Ramduth
Danni
D
Draenert
Rika
R
Le Gall
Sylvie
S
Luzzi
Graz
G
Edwards
Anne
A
Brander
Christian
C
Sewell
Andrew K
AK
Moore
Sarah
S
Mullins
James
J
Moore
Corey
C
Mallal
Simon
S
Bhardwaj
Nina
N
Yusim
Karina
K
Phillips
Rodney
R
Klenerman
Paul
P
Korber
Bette
B
Kiepiela
Photini
P
Walker
Bruce
B
Goulder
Philip
P
D016915:AIDS Vaccines; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D016384:Consensus Sequence / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens