HIV-1 Tat raises an adjuvant-free humoral immune response controlled by its core region and its ability to form cysteine-mediated oligomers.
Proteins are poor immunogens that require an adjuvant to raise an immune response. Here we show that the human immunodeficiency virus, type 1 Tat protein possesses an autoadjuvant property, and we have identified the determinants and the molecular events that are associated with this unusual property. Using a series of chemically synthesized Tat101 derivatives, we show that the core region controls the autoadjuvant phenomenon independently of the B-cell recognition and T-cell stimulation that are associated with epitopes respectively located on the N-terminal region and the cysteine-rich region. We also show that cysteine-mediated oligomerization is a key molecular event of the adjuvant-free antibody response. In particular, a Tat dimer formed by the oxidation of two cysteine residues, at position 34 only, raises an adjuvant-free antibody response that is comparable with that observed with the wild-type protein. Unlike the parent protein, the Tat dimer has no transactivating activity and remains homogeneous for several weeks in solution. This construct might be of value for the design of an adjuvant-free Tat-based vaccine. Furthermore, we suggest that the specific autoadjuvanticity determinant of Tat could be used to provide other proteins with adjuvant-free immunogenicity.
Kittiworakarn
Jongrak
J
Département d'Ingénierie et d'Etudes des Protéines, C.E. SACLAY, CEA, 91191 Gif-sur-Yvette CEDEX, France.
Lecoq
Alain
A
Moine
Gervaise
G
Thai
Robert
R
Lajeunesse
Evelyne
E
Drevet
Pascal
P
Vidaud
Claude
C
Ménez
André
A
Léonetti
Michel
M
D000276:Adjuvants, Immunologic; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D003545:Cysteine / Q000737:chemistry*; D019281:Dimerization; D000939:Epitopes / Q000737:chemistry; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry; D015696:Gene Products, tat / Q000737:chemistry / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007107:Immune System; D007124:Immunoenzyme Techniques; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D040081:Protein Array Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000737:chemistry; D054322:tat Gene Products, Human Immunodeficiency Virus
D000276:Adjuvants, Immunologic; D000939:Epitopes; D018985:Epitopes, B-Lymphocyte; D015696:Gene Products, tat; D010455:Peptides; D014764:Viral Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D003545:Cysteine; D010100:Oxygen