Sequence evolution and escape from specific immune pressure of an HIV-1 Rev epitope with extensive sequence similarity to human nucleolar protein 6.
Antigen-specific immunity is crucially important for containing viral replication in human immunodeficiency virus (HIV)-1-infected hosts. Several epitopes have been predicted for the early expressed HIV-1 proteins Tat and Rev, but few have been studied in detail. We characterized the human leukocyte antigen (HLA)-B44-restricted Rev epitope EELLKTVRL (EL9) in an HIV-1-infected subject treated with antiretroviral therapy. Interestingly, a high sequence similarity was found between the EL9 epitope and the human nucleolar protein 6 (NOL6). However, this similarity does not seem to impede immunogenicity as CD8(+)  T-cells, previously stimulated with EL9-pulsed dendritic cells, were able to specifically recognize the HIV-1 Rev epitope without cross-recognizing the human self-antigen NOL6. After the subject interrupted antiretroviral therapy and virus rebounded, mutations within the EL9 epitope were identified. Although the emerging mutations resulted in decreased or abolished T-cell recognition, they did not impair Rev protein function. Mutations leading to escape from T-cell recognition persisted for up to 124 weeks following treatment interruption. This study shows that the HLA-B44-restricted Rev CD8(+)  T-cell epitope EL9 is immunogenic notwithstanding its close resemblance to a human peptide. The epitope mutates as a consequence of dynamic interaction between T-cells and HIV-1. Clinical status, CD4(+)  T-cell count and viral load remained stable despite escape from T-cell recognition.
Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Brussels, Belgium.
S D
SD
Allard
A L
AL
de Goede
B
B
De Keersmaecker
C
C
Heirman
P
P
Lacor
A D M E
AD
Osterhaus
C
C
Demanet
K
K
Thielemans
R A
RA
Gruters
J L
JL
Aerts
D000595:Amino Acid Sequence; D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage; D001483:Base Sequence; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology*
D044966:Anti-Retroviral Agents; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; C460901:NOL6 protein, human; D009687:Nuclear Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus