Abstract
Costimulatory molecules play a central role in the development of cellular immunity. Understanding how costimulatory pathways can be directed to positively influence the immune response may be critical for the generation of an effective HIV vaccine. Here, we evaluated the ability of intravenous administration of a blocking monoclonal antibody (mAb) directed against the negative costimulatory molecule CTLA-4, and an agonist mAb directed against the positive costimulatory molecule 4-1BB, either alone or in combination, to augment intramuscular SIV DNA immunizations. We then tested the ability these of these responses to impact a high-dose SIVmac251 challenge. Following immunization, the groups infused with the anti-4-1BB mAb exhibited enhanced IFN-γ responses compared to the DNA vaccine only group. Interestingly, although CTLA-4 blockade alone did not enhance IFN-γ responses it did increase the proliferative capacity of the CD4+ and CD8+ T cells. The combination of both mAbs enhanced the magnitude of the polyfunctional CD8+ T cell response. Following challenge, the group that received both mAbs exhibited a significant, ∼2.0 log, decrease in plasma viral load compared to the naïve group the included complete suppression of viral load in some animals. Furthermore, the use of the CTLA-4 blocking antibody resulted in significantly higher viral loads during chronic infection compared to animals that received the 4-1BB mAb, likely due to the higher CD4+ T cell proliferative responses which were driven by this adjuvant following immunization. These novel studies show that these adjuvants induce differential modulation of immune responses, which have dramatically different consequences for control of SIV replication, suggesting important implications for HIV vaccine development.
Highlights
Costimulatory molecules play an important role in the development of antiviral cellular immunity, which has been extensively studied in the context of cancer immune therapy
On the day of each immunization, as well as two days later, macaques were infused with 10 mg/kg of an agonist anti-4-1BB monoclonal antibody (mAb) (4-1BB), a blocking anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) mAb (CTLA-4), both antibodies (Combo), or without (DNA) antibodies
Cell-mediated immunity, CD8+ T cell-mediated immunity, has been implicated in controlling HIV replication in humans and has been shown to be capable of inhibiting viral replication in SIV-infected macaques [15,16], suggesting that vaccines targeting cellular immunity may be beneficial for controlling HIV infection
Summary
Costimulatory molecules play an important role in the development of antiviral cellular immunity, which has been extensively studied in the context of cancer immune therapy. In the chronic phase of infection, the CTLA-4 immunized group exhibited high viral loads that were comparable to the un-immunized controls and were significantly higher than the 4-1BB or the combination adjuvant groups This suggests that a vaccine response that induces a strong effector response, i.e. cytokine production, may be more protective than a response that induces highly proliferative CD4+ T cells, which may serve as targets for SIV infection. Overall more than half the animals receiving 4-1BB antibodies alone or in combination with CTLA-4 antibodies (7/ 12) were able to completely suppress viral replication to background levels by 25 weeks post challenge This outcome suggests that vaccine driven CD4+ T cell proliferation alone may not be beneficial for an HIV vaccine, whereas the induction of a strong T cell effector response in conjunction with proliferative capacity looks to be an important strategy to pursue for HIV vaccination
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