An alternative and effective HIV vaccination approach based on inhibition of antigen presentation attenuators in dendritic cells.
BACKGROUND
Current efforts to develop HIV vaccines that seek to stimulate immune responses have been disappointing, underscoring the inability of natural immune responses to control HIV-1 infection. Here we tested an alternative strategy to induce anti-HIV immune responses by inhibiting a host's natural immune inhibitor.


RESULTS
We used small interfering RNA (siRNA) to inhibit suppressor of cytokine signaling (SOCS) 1, a key negative regulator of the JAK/STAT pathway, and investigated the effect of this silencing on the ability of dendritic cells (DCs) to induce anti-HIV-1 immunity. We found that SOCS1-silenced DCs broadly induced enhanced HIV-1 envelope (Env)-specific CD8+ cytotoxic T lymphocytes and CD4+ T helper cells, as well as antibody responses, in mice. Importantly, SOCS1-silenced DCs were more resistant to HIV Env-mediated suppression and were capable of inducing memory HIV Env-specific antibody and T cell responses. SOCS1-restricted signaling, as well as production of proinflammatory cytokines such as interleukin-12 by DCs, play a critical role in regulating the anti-HIV immune response. Furthermore, the potency of HIV DNA vaccination is significantly enhanced by coimmunization with SOCS1 siRNA expressor DNA.


CONCLUSIONS
This study demonstrates that SOCS1 functions as an antigen presentation attenuator to control both HIV-1-specific humoral and cellular responses. This study represents the first, to our knowledge, attempt to elicit HIV-specific T cell and antibody responses by inhibiting a host's antigen presentation attenuator, which may open a new and alternative avenue to develop effective therapeutic and prophylactic HIV vaccines.
Song
Xiao-Tong
XT
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
Evel-Kabler
Kevin
K
Rollins
Lisa
L
Aldrich
Melissa
M
Gao
Feng
F
Huang
Xue F
XF
Chen
Si-Yi
SY
D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic; D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination / Q000379:methods*
D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D015699:HIV Envelope Protein gp120; D034741:RNA, Small Interfering; D053707:Receptors, Interleukin-12; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12