Defining the role of myeloid cells in potentiating T-cell immunity and EcoHIV evasion from vaccine-induced protection

Abstract

Acquired immune deficiency syndrome (AIDS) is one of the most lethal infectious diseases since 1981. Despite of the ongoing research, the development of effective vaccine and regiment for complete virus eradication remains challenging. Previous findings of the research team reported that both sPD1- and sΔ42PD1-based DNA vaccines could potentiate HIV antigen-specific cytotoxic CD8+ T lymphocytes with significant improvement in quantity and quality. This confers to not only significant protection against lethal vaccinia viral challenges, but also curing of mesothelioma (an antigen-expressing malignant cancer) in mouse models. However, the underlying mechanism of these improvements remains unclear, and the effectiveness of these vaccine in exerting protection against HIV/AIDS are yet to be elucidated.

The current study therefore further investigated and compared sPD1- and sΔ42PD1-based vaccines with conventional vaccine, aiming to determine whether sPD1- or sΔ42PD1-based vaccines could prevent HIV infection in HIV/mice models. Moreover, what are the roles of functional DCs in shaping anti-HIV CD8+ T cell memory and breadth for protection, and the mechanism of viral evasion from vaccine induced protection were also investigated. Results showed that sΔ42PD1-based vaccine induced a higher frequency and broadly-reactive antigen-specific CD8+ T cells compared with sPD1-based vaccine. On the other hand, sPD1-based vaccine induced higher IFN-γ+CD8+ T cells frequency and conferred better protection against EcoHIV infection. Further longitudinal analysis of DCs showed that both sPD1 and sΔ42PD1 enhanced monocytes-derived DCs (Mo-DCs) migration into spleens when compared with control vaccines. However, sPD1 based vaccine preferentially promoted CD8+ conventional DCs (cDCs) maturation, whilst sΔ42PD1-based vaccine activated Mo-DCs to induce stronger CD4+/CD8+ T cells proliferation and cytokine release. Interestingly, EcoHIV challenge following prophylactic vaccination continued to preferentially stimulate CD8+ cDCs in recipients received sPD1-based vaccine. On the other hand, Mo-DCs were better stimulated in sΔ42PD1-based vaccine recipients. These results suggest that whilst Mo-DCs likely play a major role in sΔ42PD1-potientated CD8 T cells response, sPD1-based vaccine has an advantage in engaging CD8+ cDCs to enhance T cell immunity during vaccination and possibly infection for viral elimination.

Further detailed investigation of the PD1-based vaccine showed that although high frequencies of virus-specific CD8+ T cells were potently induced with significant responses in eliminating EcoHIV infected cells, the proviral elimination was mainly observed within 7 days post infection (dpi). This was followed by up-regulated PD1/Tim3 on both CD4+ and CD8+ T cells, diminished CD8+ T cell number and function, and prolonged proviral survival. Mechanistically, multiple DC subsets were efficiently activated and initiated virus-specific CD8+ T cells recall response. However, myeloid cells and primarily monocytes quickly expanded and persisted over time with T cell suppressive function. Meantime, EcoHIV infected not only CD4+ T cells but also myeloid cells, which were resistant to CD8+ T cells-mediated killing.

In summary, the current studies revealed the underlying mechanisms of potentiating functional CD8+ T cells in terms of quantity and quality by sPD1- and sΔ42PD1-based vaccine. The strategy of viral evasion of vaccine-induced antiviral immunity, identify CD8+ DCs as a potential target for design of effective vaccine, and myeloid cells for HIV/AIDS immunotherapy were also elucidated.