Objective: To investigate the potential to induce additional cytotoxic T-lymphocyte (CTL) immunity during chronic HIV-1 infection.
Design: We selected infrequently targeted or subdominant but conserved HLA-A*0201-binding epitopes in Gag, Pol, Env, Vpu and Vif. These relatively immune silent epitopes were modified as anchor-optimized peptides to improve immunogenicity and delivered on autologous monocyte-derived dendritic cells (MDDCs).
Methods: Twelve treatment-naïve HLA-A*0201 HIV-1-infected Danish individuals received 1 × 107 MDDCs subcutaneously (s.c.) (weeks 0, 2, 4 and 8), pulsed with seven CD8+ T-cell epitopes and three CD4+ T-cell epitopes. Epitope-specific responses were evaluated by intracellular cytokine staining for interferon-γ, tumor necrosis factor α and interleukin-2 and/or pentamer labeling 3 weeks prior to, 10 weeks after and 32 weeks after the first immunization.
Results: Previously undetected T-cell responses specific for one or more epitopes were induced in all 12 individuals. Half of the participants had sustained CD4+ T-cell responses 32 weeks after immunization. No severe adverse effects were observed. No overall or sustained change in viral load or CD4+ T-cell counts was observed.
Conclusion: These data show that it is possible to generate new T-cell responses in treatment-naive HIV-1-infected individuals despite high viral loads, and thereby redirect immunity to target new multiple and rationally selected subdominant CTL epitopes. Further optimization could lead to stronger and more durable cellular responses to selected epitopes with the potential to control viral replication and prevent disease in HIV-1-infected individuals.
aDepartment of Virology, Statens Serum Institut, Denmark
bInstitute for International Health, Immunology and Microbiology, University of Copenhagen, Denmark
cCenter for Cancer Immune Therapy, University Hospital Herlev, Denmark
dDepartment of Infectious Diseases, University Hospital Copenhagen, Denmark
eDepartment of Infectious Diseases, University Hospital Hvidovre, Copenhagen, Denmark.
Received 2 April, 2009
Revised 30 April, 2009
Accepted 30 April, 2009
Correspondence to Anders Fomsgaard, Virus Research and Development Laboratory, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen, Denmark. Tel: +45 32683460; fax: +45 32683148; e-mail: email@example.com