Journal
PLOS MEDICINE
Volume 3, Issue 1, Pages 76-93Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.0030011
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Funding
- NHLBI NIH HHS [T32 HL092332] Funding Source: Medline
- NIAID NIH HHS [R01 AI048480, T32-AI07495, R01 AI048711, R01AI48711, T32 AI007495, R21 AI055386, R01AI48480] Funding Source: Medline
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI048711, T32AI007495, R01AI048480, R21AI055386] Funding Source: NIH RePORTER
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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. Methods and Findings 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.
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