Strong Th1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy

Abstract

Activated CD4 T cells are a major target of HIV infection. Results from the Step HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced IFNγ+ CD4 T cells (Th1 cells) which rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal Th1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. Following intravaginal or intrarectal SIV/SHIV challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific Th1 cells but not in animals that had higher frequencies of Th1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer Th1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine-induced Th1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.

One sentence summary

Vaccine-induced IFNγ+ CD4 T cells migrate to and persist in mucosal tissue and negatively associate with protection against SIV