Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes

TY - JOUR

T1 - Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes

AU - Kloverpris, Henrik

AU - Karlsson, Ingrid

AU - Bonde, Jesper

AU - Thorn, Mette

AU - Vinner, Lasse

AU - Pedersen, Anders

AU - Hentze, Julie

AU - Andresen, Betina

AU - Svane, Inge

AU - Gerstoft, Jan

AU - Kronborg, Gitte

AU - Fomsgaard, Anders

AU - Kloverpris, Henrik

AU - Karlsson, Ingrid

AU - Bonde, Jesper

AU - Thorn, Mette

AU - Vinner, Lasse

AU - Pedersen, Anders E

AU - Hentze, Julie L

AU - Andresen, Betina S

AU - Svane, Inge M

AU - Gerstoft, Jan

AU - Kronborg, Gitte

AU - Fomsgaard, Anders

PY - 2009

Y1 - 2009

N2 - 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 x 10 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-gamma, tumor necrosis factor alpha 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.

AB - 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 x 10 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-gamma, tumor necrosis factor alpha 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.

U2 - 10.1097/QAD.0b013e32832d9b00

DO - 10.1097/QAD.0b013e32832d9b00

M3 - Journal article

C2 - 19528789

SN - 0269-9370

VL - 23

SP - 1329

EP - 1340

JO - AIDS

JF - AIDS

IS - 11

ER -