Broadening of the T-cell repertoire to HIV-1 Gag p24 by vaccination of HLA-A2/DR transgenic mice with overlapping peptides in the CAF05 adjuvant.

John Stambas,Karen S Korsholm,Claus Aagaard,Ingrid Karlsson,Peter Andersen,Else Marie Agger,Anders Fomsgaard,Lea Brandt,Sheila T Tang

doi:10.1371/journal.pone.0063575

Abstract

Induction of broad T-cell immune responses is regarded as critical for vaccines against the human immunodeficiency virus type 1 (HIV-1) which exhibit high diversity and, therefore, focus has been on inducing cytotoxic CD8 T-cell responses against the more conserved parts of the virus, such as the Gag protein. Herein, we have used the p24 protein which contains a range of conserved T-cell epitopes. We demonstrate that a vaccine of HIV-1 subtype B consensus group-specific antigen (Gag) p24 protein with the CD8-inducing liposomal cationic adjuvant formulation (CAF) 05, induces both CD4 and CD8 T-cell responses in CB6F1 mice. The adjuvanted vaccine also induced functional antigen-specific cytotoxicity in vivo. Furthermore, we found that when fragmenting the Gag p24 protein into overlapping Gag p24 peptides, a broader T-cell epitope specificity was induced in the humanized human leukocyte antigen (HLA)-A2/DR-transgenic mouse model. Thus, combining overlapping Gag p24 peptides with CAF05 appears to be a promising and simple strategy for inducing broader T-cell responses to multiple conserved epitopes which will be relevant for both prophylactic and therapeutic HIV-1 vaccines.

Highlights

Despite increasing availability of antiretroviral treatment (ART), the acquired immunodeficiency syndrome (AIDS) is still the underlying cause for more deaths worldwide than any other infectious disease [1]
We found that overlapping Gag p24 peptides (OLGa) in CAF05 resulted in both a higher and broader T-cell response when compared with whole Gag p24 protein as the antigen
Both adjuvanted vaccines induced a good Gag p24-specific IFN-c release but the CAF05 adjuvant was significantly better than CAF01 when the cells were restimulated with antigen concentrations of 0.5 mg/ml or higher

Summary

Introduction

Despite increasing availability of antiretroviral treatment (ART), the acquired immunodeficiency syndrome (AIDS) is still the underlying cause for more deaths worldwide than any other infectious disease [1] Vaccination, both prophylactic and therapeutic, is an important alternative or supplement to conventional treatment and in addition, it is the only intervention that can provide immunological memory. Whereas induction of antibodies against the envelope protein (Env) is required for prophylactic vaccines, T-cell responses are important for immune control of HIV-1 replication [2,3,4] and different T-cell activating therapeutic vaccines are being developed and tested [5,6,7] It is debated which are the most effective antigens to target for T-cell based HIV-1 vaccines. The ability to mount multiple simian immunodeficiency virus (SIV)

Methods

Results

Conclusion