Mother-to-child transmission of HIV infection and CTL escape through HLA-A2-SLYNTVATL epitope sequence variation.
Cytotoxic T lymphocytes (CTL) play a central role in containment of HIV infection. Evasion of the immune response by CTL escape is associated with progression to disease. It is therefore hypothesised that transmitted viruses encode escape mutations within epitopes that are required for successful control of viraemia. In order to test this hypothesis, escape through the dominant HLA-A2-restricted CTL epitope SLYNTVATL (p17 Gag residues 77-85 SL9) in the setting of mother-to-child-transmission (MTCT) was investigated. Initial data from two families in which the HIV-infected mother expressed HLA-A*0201 and had transmitted the virus to other family members were consistent with this hypothesis. In addition, analysis of the gag sequence phylogeny in one family demonstrated that CTL escape variants can be successfully transmitted both horizontally and vertically. To test the hypothesis further, a larger cohort of transmitting mothers (n=8) and non-transmitters (n=14) were studied. Variation within the SL9 epitope was associated with expression of HLA-A2 (P=0.04) but overall no clear link between variation from the SL9 consensus sequence and MTCT was established. However, the high level of background diversity within p17 Gag served to obscure any possible association between escape and MTCT. In conclusion, these studies highlighted the obstacles to demonstrating CTL escape arising at this particular epitope. Alternative strategies likely to be more definitive are discussed.
Goulder
P J
PJ
Department of Paediatrics, Nuffield Department of Medicine, Level 7, Room 7615, John Radcliffe Hospital, Oxford OX3 9DU, UK. philip.goulder@ndm.ox.ac.uk
Pasquier
C
C
Holmes
E C
EC
Liang
B
B
Tang
Y
Y
Izopet
J
J
Saune
K
K
Rosenberg
E S
ES
Burchett
S K
SK
McIntosh
K
K
Barnardo
M
M
Bunce
M
M
Walker
B D
BD
Brander
C
C
Phillips
R E
RE
D000595:Amino Acid Sequence; D000940:Antigenic Variation; D002648:Child; D002675:Child, Preschool; D000939:Epitopes / Q000235:genetics; D005260:Female; D015683:Gene Products, gag / Q000235:genetics*; D006678:HIV / Q000235:genetics / Q000276:immunology; D015488:HIV Antigens / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000635:transmission* / Q000821:virology; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D009154:Mutation; D010375:Pedigree; D010802:Phylogeny; D011247:Pregnancy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus
D000939:Epitopes; D015683:Gene Products, gag; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1