Identification of immunogenic HLA-B7 "Achilles' heel" epitopes within highly conserved regions of HIV

TY - JOUR

T1 - Identification of immunogenic HLA-B7 "Achilles' heel" epitopes within highly conserved regions of HIV

AU - De Groot, Anne S

AU - Rivera, Daniel S

AU - McMurry, Julie A

AU - Buus, Søren

AU - Martin, William

N1 - Keywords: Algorithms; Amino Acid Sequence; Conserved Sequence; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes, T-Lymphocyte; HIV Antigens; HIV Infections; HIV-1; HLA-B7 Antigen; Humans; Interferon-gamma; Leukocytes, Mononuclear; Polymorphism, Genetic

PY - 2008

Y1 - 2008

N2 - Genetic polymorphisms in class I human leukocyte antigen molecules (HLA) have been shown to determine susceptibility to HIV infection as well as the rate of progression to AIDS. In particular, the HLA-B7 supertype has been shown to be associated with high viral loads and rapid progression to disease. Using a multiplatform in silico/in vitro approach, we have prospectively identified 45 highly conserved, putative HLA-B7 restricted HIV CTL epitopes and evaluated them in HLA binding and ELISpot assays. All 45 epitopes (100%) bound to HLA-B7 in cell-based HLA binding assays: 28 (62%) bound with high affinity, 6 (13%) peptides bound with medium affinity and 11 (24%) bound with low affinity. Forty of the 45 peptides (88%) stimulated a IFN-gamma response in PBMC from at least one subject. Eighteen of these 40 epitopes have not been previously described; an additional eight epitopes have not been previously described as restricted by B7. The HLA-B7 restricted epitopes discovered using this in silico screening approach are highly conserved across strains and clades of HIV as well as conserved in the HIV genome over the 20 years since HIV-1 isolates were first sequenced. This study demonstrates that it is possible to select a broad range of HLA-B7 restricted epitopes that comprise stable elements in the rapidly mutating HIV genome. The most immunogenic of these epitopes will be included in the GAIA multi-epitope vaccine.

AB - Genetic polymorphisms in class I human leukocyte antigen molecules (HLA) have been shown to determine susceptibility to HIV infection as well as the rate of progression to AIDS. In particular, the HLA-B7 supertype has been shown to be associated with high viral loads and rapid progression to disease. Using a multiplatform in silico/in vitro approach, we have prospectively identified 45 highly conserved, putative HLA-B7 restricted HIV CTL epitopes and evaluated them in HLA binding and ELISpot assays. All 45 epitopes (100%) bound to HLA-B7 in cell-based HLA binding assays: 28 (62%) bound with high affinity, 6 (13%) peptides bound with medium affinity and 11 (24%) bound with low affinity. Forty of the 45 peptides (88%) stimulated a IFN-gamma response in PBMC from at least one subject. Eighteen of these 40 epitopes have not been previously described; an additional eight epitopes have not been previously described as restricted by B7. The HLA-B7 restricted epitopes discovered using this in silico screening approach are highly conserved across strains and clades of HIV as well as conserved in the HIV genome over the 20 years since HIV-1 isolates were first sequenced. This study demonstrates that it is possible to select a broad range of HLA-B7 restricted epitopes that comprise stable elements in the rapidly mutating HIV genome. The most immunogenic of these epitopes will be included in the GAIA multi-epitope vaccine.

U2 - 10.1016/j.vaccine.2007.12.004

DO - 10.1016/j.vaccine.2007.12.004

M3 - Journal article

C2 - 18206276

SN - 0264-410X

VL - 26

SP - 3059

EP - 3071

JO - Vaccine

JF - Vaccine

IS - 24

ER -