Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes.
OBJECTIVE
To investigate the potential to induce additional cytotoxic T-lymphocyte (CTL) immunity during chronic HIV-1 infection.


METHODS
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.


CONCLUSIONS
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.
Kloverpris
Henrik
H
Department of Virology, Statens Serum Institut, University of Copenhagen, Denmark.
Karlsson
Ingrid
I
Bonde
Jesper
J
Thorn
Mette
M
Vinner
Lasse
L
Pedersen
Anders E
AE
Hentze
Julie L
JL
Andresen
Betina S
BS
Svane
Inge M
IM
Gerstoft
Jan
J
Kronborg
Gitte
G
Fomsgaard
Anders
A
D016915:AIDS Vaccines; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D019562:Viral Load
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte