Immunomodulatory Tr1 CD4 T cells induced by engineered V1-deleted HIV vaccine candidate decrease the risk of SIV acquisition in macaques 2267572

Abstract

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. 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. 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. 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. n/a Vaccines and Immunotherapy (VAC)