Staff Scientist NCI, CCR, NIH Bethesda, Maryland, United States
Disclosure(s):
Massimiliano Bissa, PhD: No financial relationships to disclose
Introduction/Rationale: The development of an effective anti-HIV vaccine remains a critical tool to halt the HIV epidemic, particularly due to the limits of the PrEP strategies. CD4+ T lymphocytes play a crucial role in vaccine efficacy; however, they are also the primary target cells for HIV infection. Given these opposing roles, we hypothesized that an in-depth characterization of CD4+ T cell responses to vaccination will elucidate mechanisms of protection.
Methods: To test this hypothesis, we immunized rhesus macaques using a prime-boost strategy that included a DV1-DNA prime and boosts with ALVAC alone or in combination with DV1-gp120 protein, followed by intravaginal exposures to SIVmac251. We then integrated data obtained by flow cytometry and plasma proteome analyses, as well as transcriptome and chromatin accessibility analyses of CD3+ cells, to investigate how the vaccine shapes the CD4+ T cell immunity and how these responses cooperate in reducing the acquisition.
Results: We found that DV1 DNA/ALVAC/gp120 vaccine elicited envelope-specific immunomodulatory Tr1 CD4+ T cells, and that total Tr1 responses were associated with a reduced risk of viral acquisition. Transcriptome analyses of CD3+ cells identified vaccine-induced Tr1, as well as IL-27, gene signatures that were associated with a reduced risk, confirming the protective role of these cells. Furthermore, the study of the epigenetic landscape of CD3+ cells revealed that the epigenetic reprogramming of enhancer region upstream of the transcription factors BATF and IRF-1, which are involved in the development of Tr1 cells, correlated with lower viral acquisition.
Conclusion: These data suggest that immunoinhibitory Tr1 cells contribute to vaccine efficacy by decreasing inflammation and potentially counteracting the development and recruitment of HIV target cells.
